EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC
This gene encodes a membrane-bound protein that is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces. These proteins also play a role in intracellular signaling. This protein is expressed on the apical surface of epithelial cells that line the mucosal surfaces of many different tissues including lung, breast stomach and pancreas. This protein is proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex. The N-terminal alpha subunit functions in cell-adhesion and the C-terminal beta subunit is involved in cell signaling. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. This gene is known to contain a highly polymorphic variable number tandem repeats (VNTR) domain. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]
MUC1 is implicated in: - apical plasma membrane
- cell surface
- cellular protein metabolic process
- DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- extracellular region
- Golgi lumen
- integral to plasma membrane
- negative regulation of apoptotic process
- negative regulation of transcription by competitive promoter binding
- nuclear chromatin
- O-glycan processing
- p53 binding
- positive regulation of histone H4 acetylation
- positive regulation of transcription from RNA polymerase II promoter in response to stress
- post-translational protein modification
- protein binding
- regulation of transcription from RNA polymerase II promoter in response to stress
- RNA polymerase II core promoter proximal region sequence-specific DNA binding
- transcription cofactor activity
Data from Gene Ontology via CGAP [Hide]
MUC1 is sometimes involved in t(1;14) translocations in Non Hodgkin's Lymphoma, but otherwise there aren't many reports of the gene being regularly mutated in cancer. However, MUC1 protein is overexpressed in a diverse range of carcinomas and expression of MUC1 is a prognostic factor in several types of cancer. Expression of MUC1 can play an important role in the development of resistance to chemotherapy. Also, MUC1 expression in cancer cells is associated with avoidance of immune defenses (e.g. Suzuki et al, 2012) and MUC1 can bind to p53 resulting in inhibition of p53-mediated apoptosis (Wei et al, 2005). Increased expression of MUC1 also promotes cancer cell mobility promoting the formation of metastases (Schroeder et al, 2003). MUC1 is a potential target for immunotherapy.
MUC1 Expression in Breast CancerPrognostic High levels of MUC1 protein are expressed in >70% of breast cancers.
In a series of 691 patients Sinn et al (2013) found high levels of MUC1 were more frequent in hormone-receptor-positive breast cancers and that MUC1 protein and mRNA expression were independently prognostic for overall survival in multivariate analysis.
MUC1 and ImmunotherapyTherapy Since its discovery MUC1 has been an attractive target for antitumor immunotherapy (e.g. Karanikas et al, 1997) - in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 and vaccination strategies have been developed and are now being tested in clinical trials against different types of cancer (Roulois et al (2013) [Full Text])
MUC1 overexpression in Pancreatic CancerPrognostic MUC1 is overexpressed in >60% of human pancreatic cancers, and is associated with poor prognosis, enhanced metastasis and chemoresistance - (Nath et al (2013)) reported that pancreatic cancers with high levels of MUC1 were associated with increased drug resistance, and suggest that MUC1 plays a role in upregulating MRP1, a protein involved in drug resistance.
MUC1 and Colorectal CancerPrognostic MUC1 expression was associated with advanced disease and poor prognosis in a number of studies. For example Duncan et al (2007) found MUC1 expression was an independent prognostic factor in a series of 462 colorectal cancer patients, even when vascular invasion was included in multivariate analysis.
MUC1 and Lung CancerPrognostic Hirasawa et al (2000) found that levels of anti-MUC1 antibody in serium was a significant prognostic factor for Non-Small Cell Lung Cancer (NSCLC). Situ et al (2011) evaluated the expression of MUC1 in 178 stage IB NSCLC and found that high MUC1 expression was more common in adenocarcinomas than squamous cell carcinomas. Up-regulated expression of MUC1 was a significant adverse prognostic factor for survival and disease-free survival in both univariate and multivariate analysis.
MUC1 and Gastric Cancer There are some conflicting results about the clinical relevance of MUC1 expression in gastric carcinoma in the literature. Some studies report MUC1 expression levels are associated with tumor cell differentiation, lymph note involvement and distant metastases. Ilhan et al. (2010) notes that MUC1 is strongly expressed in normal gastric epithelium. There are also reports linking polymorphisms in MUC1 to susceptibility to gastric cancer.
MUC1 and Bladder Cancer Simms et al (1999) and some other subsequent studies found that whilst serum MUC1 is not as useful tumour marker for screening/diagnosis of bladder cancer, levels are higher in advanced disease. Suzuki et al (2012) reported that binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans reduces the interaction with Natural Killer (NK) cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to C2GnT-expressing bladder cancer cells. This enables tumor cells to evade NK cell immunity and survive longer in blood circulation, thereby metastasis.
MUC1 polymorphisms and cancer suseptability? Mitsuta et al (2005) found that a large MUC1 allele was associated with susceptibility to lung adenocarcinoma and poor prognosis based on a study of 52 NSCLC patients in Japan compared to 52 controls. Xu et al (2009) reported that risk of gastric cancer is associated with the MUC1 568 A/G polymorphism. Li et al (2012) reported a protective effect of the rs2070803 polymorphism in MUC1 in a case-control study of 300 Chinese gastric cancer patients and 300 controls. In a a genome-wide association study Saeki et al (2013) reported polymorphisms in MUC1 and PSCA (8q24) were linked to diffuse-type gastric cancer in a Japanese population.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
MUC1 OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
MUC1 International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
MUC1 Cancer Genome Anatomy Project, NCI Gene Summary
MUC1 COSMIC, Sanger Institute Somatic mutation information and related details
MUC1 TICdb, Universidad de Navarra Search the database of Translocation breakpoints In Cancer for "MUC1"
MUC1 Epigenomics, NCBI Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: MUC1 (cancer-related)
Nakamura K, Yamashita K, Sawaki H, et al. Aberrant methylation of GCNT2 is tightly related to lymph node metastasis of primary CRC. Anticancer Res. 2015; 35(3):1411-21 [PubMed] Related Publications
BACKGROUND: Glycoprotein expression profile is dramatically altered in human cancers; however, specific glycogenes have not been fully identified. MATERIALS AND METHODS: A comprehensive real-time polymerase chain reaction (PCR) system for glycogenes (CRPS-G) identified several outstanding glycogenes. GCNT2 was of particular interest after GCNT2 expression and epigenetics were rigorously investigated in primary colorectal cancer (CRC). RESULTS: The highlights of this work can be summarized as follows: (i) Expression of GCNT2 was remarkably suppressed. (ii) Silenced expression of GCNT2 was reactivated by combined demethylating agents. (iii) Promoter DNA methylation of GCNT2 was silenced in CRC cell lines and tissues. Hypomethylation of GCNT2 variant 2 is tightly associated with lymph node metastasis in primary CRC. (iv) GCNT2 methylation level in the normal tissues also showed a close association with that in the tumor tissues and reflected lymph node metastasis. CONCLUSION: We identified aberrant expression of GCNT2, which can be explained by promoter DNA hypermethylation. Hypomethylation of the GCNT2 variant 2 reflected lymph node metastasis of CRC in the tumor and normal tissues.
Fang CY, Tsai YD, Lin MC, et al. Inhibition of human bladder cancer growth by a suicide gene delivered by JC polyomavirus virus-like particles in a mouse model. J Urol. 2015; 193(6):2100-6 [PubMed] Related Publications
PURPOSE: Bladder cancer is one of the most common cancers of the urinary tract. The poor 5-year survival rate of invasive bladder cancer represents a challenge for bladder cancer treatment. Previous studies demonstrated that human urothelial carcinoma is susceptible to infection by JC polyomavirus. We used JC polyomavirus virus-like particles to deliver genes into human urothelial carcinoma cells for possible therapeutic investigation. MATERIALS AND METHODS: Reporter plasmids (pEGFP-N3) for expressing green fluorescent protein, LacZ expression plasmids bearing cytomegalovirus or Muc1 promoter and a functional plasmid (pUMVC1-tk) for expressing thymidine kinase were packaged into JC polyomavirus virus-like particles. Plasmid DNAs were transduced via the JC polyomavirus virus-like particles into human urothelial carcinoma cells in vitro and into xenografted human bladder tumor nodules in vivo. RESULTS: pEGFP-N3 DNA was delivered and green fluorescent protein was expressed in human urothelial carcinoma cells in vitro and in the tumor nodules of mice in vivo. The thymidine kinase transgene also functioned in vitro and in vivo after JC polyomavirus virus-like particle transduction. The thymidine kinase gene transduced urothelial carcinoma nodules were drastically reduced in the presence of acyclovir. In addition, we noted selective Muc1-LacZ expression in human urothelial carcinoma cells transduced by JC polyomavirus virus-like particles. CONCLUSIONS: These findings provide a possible future approach to human urothelial carcinoma gene therapy using JC polyomavirus virus-like particles.
Wang L, Wang B, Fang M, et al. Identification of microRNAs and target genes involved in serous ovarian carcinoma and their influence on survival. Eur J Gynaecol Oncol. 2014; 35(6):655-61 [PubMed] Related Publications
AIMS: To identify the expression of key microRNAs and their predicted target genes involved in serous ovarian carcinoma (SOC) and correlation between miRNAs and prognosis. MATERIALS AND METHODS: The authors used quantitative polymerase chain reaction (qPCR) to detect the expression of miR-145, miR-143, miR-146a, miR-93, miR-29a, miR-18a, and miR-200a in tissues of 56 primary SOC patients and 30 benign lesion patients. Four protein (MUC1, FAP, MMP2, MMP9) expressions were identified by western blotting and immunohistochemical stain. The Kaplan-Meier method was used to estimate the relationship of these miRNAs with overall survival rate. RESULTS: In SOC tissue, expression of miR-200a, miR-93, miR-146a, and miR-18a were up-regulated, while miR-145, miR-143, miR-29a were down-regulated. MUC1, FAP, MMP2, and MMP9 were overexpressed in SOC. MiR-143 or miR-145 higher expressed patients had significantly higher overall survival (OS) rates, while miR-93 or miR-200a lower expressed patients also had higher OS rates. DISCUSSION: These results suggested that several miRNAs and their regulated target transcripts may have important roles in the initiation and development of SOC. MiR-145/miR-143, miR-200a, and miR-93 could be used as prognostic biomarkers.
Kupcinskas J, Wex T, Link A, et al. PSCA and MUC1 gene polymorphisms are associated with gastric cancer and pre-malignant gastric conditions [corrected]. Anticancer Res. 2014; 34(12):7167-75 [PubMed] Related Publications
BACKGROUND/AIM: Genome-wide association studies revealed a link between gastric cancer (GC) and single nucleotide polymorphisms (SNPs) of prostate stem cell antigen (PSCA), phospholipase C epsilon-1 (PLCE1) and mucin-1 (MUC1) genes. Herein, we aimed to evaluate associations between PSCA (C>T, rs2294008; G>A, rs2976392), MUC1 (C>T, rs4072037) and PLCE1 (A>G, rs2274223) SNPs and GC or high-risk gastritis (HRAG). MATERIALS AND METHODS: Using TaqMan system, SNPs were genotyped in 252 patients with GC, 136 patients with HRAG and 246 controls. RESULTS: PSCA rs2294008 allele T was associated with risk of GC (odds ratio (OR)=1.88, p<0.001) and HRAG (OR=1.49, p=0.009). Allele A of PSCA rs2976392 was associated with development of GC (OR=1.88, p<0.001) and HRAG (OR=1.56, p<0.01). MUC1 rs4072037 allele G was protective against development of GC (OR=0.64, p=0.0005), while no differences were found for PLCE1 rs2274223. CONCLUSION: Polymorphisms of PSCA (rs2976392, rs2294008) and MUC1 (rs4072037) genes are associated with GC and HRAG.
Thondam SK, du Plessis D, Cuthbertson DJ, et al. Intracranial desmoplastic small round cell tumor presenting as a suprasellar mass. J Neurosurg. 2015; 122(4):773-7 [PubMed] Related Publications
Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive neoplasms that typically arise from abdominal and pelvic peritoneum in young adults. Other primary sites are uncommon, and an intracranial origin is exceptionally rare. Here the authors report the first case of a DSRCT presenting as a primary suprasellar tumor causing panhypopituitarism and severe bitemporal hemianopia in a young man. Macroscopic debulking of the tumor was undertaken, and histology revealed features of DSRCT. Reverse transcription polymerase chain reaction confirmed the presence of Ewing's sarcoma-Wilms tumor 1 (EWS-WT1) gene rearrangement specific to DSRCT. Postoperative whole-body imaging showed no primary malignancy elsewhere. The tumor recurred 4 months after surgery, and this was followed by cervical and mediastinal lymph node metastases. The patient died 20 months after initial presentation of rapidly progressive disease. DSRCTs should be included in the differential diagnosis of an unusual suprasellar mass in young adults. Early diagnosis is essential, and once the tumor is identified histologically, gross-total resection and radical postoperative treatment involving radiotherapy, chemotherapy, and close surveillance are required because of the lesion's potential for rapidly progressive malignancy.
Ema A, Yamashita K, Ushiku H, et al. Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer. Cancer Sci. 2014; 105(12):1591-600 [PubMed] Related Publications
Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.
Fina E, Callari M, Reduzzi C, et al. Gene expression profiling of circulating tumor cells in breast cancer. Clin Chem. 2015; 61(1):278-89 [PubMed] Related Publications
BACKGROUND: Determining the transcriptional profile of circulating tumor cells (CTCs) may allow the acquisition of clinically relevant information while overcoming tumor heterogeneity-related biases associated with use of tissue samples for biomarker assessment. However, such molecular characterization is challenging because CTCs are rare and outnumbered by blood cells. METHODS: Here, we describe a technical protocol to measure the expression of >29 000 genes in CTCs captured from whole blood with magnetic beads linked with antibodies against epithelial cell adhesion molecule (EpCAM) and the carcinoma-associated mucin, MUC1, designed to be used for CTC characterization in clinical samples. Low numbers of cells (5-200) from the MCF7 and MDA-MB-468 breast cancer cell lines were spiked in healthy donor blood samples and isolated with the AdnaTest EMT-1/Stem CellSelect kit. Gene expression profiles (GEPs) were obtained with the WG-DASL HT assay and compared with GEPs obtained from RNA isolated from cultured cell lines and unspiked samples. RESULTS: GEPs from samples containing 25 or more spiked cells correlated (r = 0.95) with cognate 100-ng RNA input samples, clustered separately from blood control samples, and allowed MCF7 and MDA-MB-468 cells to be distinguished. GEPs with comparable technical quality were also obtained in a preliminary series of clinical samples. CONCLUSIONS: Our approach allows technically reliable GEPs to be obtained from isolated CTCs for the acquisition of biologically useful information. It is reproducible and suitable for application in prospective studies to assess the clinical utility of CTC GEPs, provided that >25 CTCs can be isolated.
Mori Y, Akita K, Tanida S, et al. MUC1 protein induces urokinase-type plasminogen activator (uPA) by forming a complex with NF-κB p65 transcription factor and binding to the uPA promoter, leading to enhanced invasiveness of cancer cells. J Biol Chem. 2014; 289(51):35193-204 [PubMed] Article available free on PMC after 19/12/2015 Related Publications
Mucin 1 (MUC1) is overexpressed in various human malignant tumors and its expression is correlated with a poor prognosis. MUC1 engages in signal transduction by interacting with receptors for growth and differentiation factors, which contributes to the growth and survival of cancer cells. However, the mechanism by which MUC1 promotes cancer cell invasion remains unclear. Microarray analysis revealed that expression of urokinase-type plasminogen activator (uPA) was elevated in MUC1-overexpressing cells. Furthermore, up- and down-modulation of MUC1 expression was clearly correlated with the change of uPA expression. An immunochemical study showed that the distribution of uPA coincided with that of MUC1 in various human cancer tissues. The MUC1 C-terminal domain (MUC1-CD) was associated with nuclear factor-κB (NF-κB) p65 in MUC1-expressing cells. Chromatin immunoprecipitation (ChIP) assays demonstrated that MUC1-CD existed with NF-κB p65 on the uPA promoter. Luciferase assays indicated that the uPA transcriptional activity was correlated with the level of MUC1 expression and that this MUC1-enhancing effect on the uPA transcription was abolished by introduction of mutations into the NF-κB binding sites on the uPA promoter. These results indicate that formation of the MUC1-CD and NF-κB p65 complex enhanced nuclear translocation of NF-κB p65 and subsequent occupancy of NF-κB binding region on the uPA promoter, leading to elevated transcription of uPA. We also demonstrated that uPA induced by MUC1 enhanced the matrix metalloproteinase (MMP)-2 and -9 activities, and consequently promoted cancer cell invasion. Thus, a MUC1 co-operating NF-κB signaling pathway plays a critical role in cancer cell invasion in MUC1-expressing cells.
Li G, Zhao L, Li W, et al. Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression. Oncotarget. 2014; 5(18):8317-29 [PubMed] Article available free on PMC after 19/12/2015 Related Publications
Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.
Sapino A, Maletta F, Verdun di Cantogno L, et al. Gene status in HER2 equivocal breast carcinomas: impact of distinct recommendations and contribution of a polymerase chain reaction-based method. Oncologist. 2014; 19(11):1118-26 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.
Donepudi MS, Kondapalli K, Amos SJ, Venkanteshan P Breast cancer statistics and markers. J Cancer Res Ther. 2014 Jul-Sep; 10(3):506-11 [PubMed] Related Publications
Breast cancer is one of the familiar diseases in women. Incidence and mortality due to cancer, particularly breast cancer has been increasing for last 50 years, even though there is a lacuna in the diagnosis of breast cancer at early stages. According to World Health Organization (WHO) 2012 reports, breast cancer is the leading cause of death in women, accounting 23% of all cancer deaths. In Asia, one in every three women faces the risk of breast cancer in their lifetime as per reports of WHO 2012. Here, the review is been focused on different breast cancer markers, that is, tissue markers (hormone receptors, human epidermal growth factor-2, urokinase plasminogen activator, plasminogen activator inhibitor, p53 and cathepsin D), genetic markers (BRAC1 and 2 and gene expression microarray technique, etc.), and serum markers (CA 15.3, BR 27.29, MCA, CA 549, carcinoembryonic antigen, oncoproteins, and cytokeratins) used in present diagnosis, but none of the mentioned markers can diagnose breast cancer at an early stage. There is a disquieting need for the identification of best diagnosing marker, which can be able to diagnose even in early stage of breast carcinogenesis.
Kanazawa K, Yokouchi H, Wang X, et al. Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for non-squamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902. Cancer Chemother Pharmacol. 2014; 74(6):1149-57 [PubMed] Related Publications
PURPOSE: This phase II study evaluated the response rate (RR) and safety of combination therapy with carboplatin (CBDCA) and pemetrexed (PEM) in Japanese patients with non-squamous non-small cell lung cancer (non-sq NSCLC). Further, the relationship between therapy efficacy/toxicity and genetic polymorphisms associated with PEM metabolism was analyzed. METHODS: Forty-one patients received CBDCA at a dose targeting an area under the concentration-time curve of 5 mg/mL × min and PEM of 500 mg/m(2) on day 1 every 3 weeks. Single-nucleotide polymorphisms of the thymidylate synthase (TYMS) coding gene, the variable number of tandem repeat (VNTR) in the TYMS, and the methylenetetrahydrofolate reductase (MTHFR) coding gene were analyzed. RESULTS: The overall RR was 36.6 %. Median progression-free survival and median survival time were 4.7 months [95 % confidence interval (CI) 3.9-5.6 months] and 16.2 months (95 % CI 6.1-26.2 months), respectively. Epidermal growth factor receptor gene mutations were detected in 6 patients (14.6 %). The VNTR in the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038). CONCLUSIONS: This combination therapy was effective and tolerable in patients with advanced non-sq NSCLC. The VNTR in the TYMS appears to be a predictive factor for anemia and thrombocytopenia in patients treated with this regimen.
Jeong JY, Suh YL, Hong SW Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report. Neuropathology. 2014; 34(4):398-405 [PubMed] Related Publications
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.AT/RT typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA.
Sakakibara S, Tosato G Contribution of viral mimics of cellular genes to KSHV infection and disease. Viruses. 2014; 6(9):3472-86 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV, also named Human herpesvirus 8 HHV-8) is the cause of Kaposi sarcoma (KS), the most common malignancy in HIV-infected individuals worldwide, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV is a double-stranded DNA virus that encodes several homologues of cellular proteins. The structural similarity between viral and host proteins explains why some viral homologues function as their host counterparts, but sometimes at unusual anatomical sites and inappropriate times. In other cases, structural modification in the viral proteins can suppress or override the function of the host homologue, contributing to KSHV-related diseases. For example, viral IL-6 (vIL-6) is sufficiently different from human IL-6 to activate gp130 signaling independent of the α subunit. As a consequence, vIL-6 can activate many cell types that are unresponsive to cellular IL-6, contributing to MCD disease manifestations. Here, we discuss the molecular biology of KSHV homologues of cellular products as conduits of virus/host interaction with a focus on identifying new strategies for therapy of KS and other KSHV-related diseases.
Yamamoto K, Seike M, Takeuchi S, et al. MiR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma. Oncol Rep. 2014; 32(6):2365-72 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence in Japan. In this study, we performed gene and microRNA (miRNA) expression profiling to identify novel therapeutic targets in MPM cells. Based on relative sensitivities to pemetrexed (PEM) and the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), 211H cells were determined to be the only sensitive MPM cell line out of the 6 tested. On the same series of cell lines, we performed whole genome transcriptomic profiling via DNA microarrays and pathway analysis of the derived data. Of particular note, IL-18 gene expression levels were significantly higher in the cell lines that were either drug resistant or displayed intermediate sensitivity, compared to the sensitive 211H cell line. Pathway analysis revealed IL-18 as an important gene associated with drug sensitivity of MPM cells. A relationship between IL-18 overexpression and drug resistance was also observed following targeted assessment of 10 cytokine genes using quantitative RT-PCR. miRNA expression profiles were evaluated in the MPM cell line panel in order to discern the mechanism of IL-18 induction in the drug-resistant lines. We found that miR-379 and miR-411 belonged to the same cluster of miRNAs located on chromosome 14q32 that commonly target the IL-18 gene. Luciferase reporter assays revealed that miR-379 and miR-411 directly target the IL-18 gene. Introduction of miR-379 plus miR-411, as well as IL-18 silencing, significantly suppressed the invasive capacity of MESO1 cells in vitro. Furthermore, the use of either PEM or SAHA together with miR-379 plus miR-411 mimics mediated increased sensitivity to these drugs in MESO1 cells. These results suggest that the miR-379/411 cluster may provide new therapeutic opportunities for advanced MPM patients, depending on the nature of IL-18 gene expression.
Agaram NP, Chen HW, Zhang L, et al. EWSR1-PBX3: a novel gene fusion in myoepithelial tumors. Genes Chromosomes Cancer. 2015; 54(2):63-71 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The genetics of myoepithelial tumors (ME) of soft tissue and bone have recently been investigated, with EWSR1-related gene fusions being seen in approximately half of the tumors. The fusion partners of EWSR1 so far described include POU5F1, PBX1, ZNF444 and, in a rare case, ATF1. We investigated by RNA sequencing an index case of EWSR1-rearranged ME of the tibia, lacking a known fusion partner, and identified a novel EWSR1-PBX3 fusion. The fusion was further validated by reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization (FISH). To evaluate if this is a recurrent event, an additional cohort of 22 EWSR1-rearranged ME cases lacking a fusion partner were screened by FISH for abnormalities in PBX3 gene. Thus, two additional cases were identified showing an EWSR1-PBX3 gene fusion. One of them was also intraosseous involving the ankle, while the other occurred in the soft tissue of the index finger. The morphology of the EWSR1-PBX3 fusion positive cases showed similar findings, with nests or sheets of epithelioid to spindle cells in a partially myxoid to collagenous matrix. All three cases showed expression of S100 and EMA by immunohistochemistry. In summary, we report a novel EWSR1-PBX3 gene fusion in a small subset of ME, thereby expanding the spectrum of EWSR1-related gene fusions seen in these tumors. This gene fusion seems to occur preferentially in skeletal ME, with two of the three study cases occurring in intraosseous locations.
Shon W, Salomão DR WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases. Int J Dermatol. 2014; 53(10):1228-34 [PubMed] Related Publications
BACKGROUND: Endocrine mucin-producing sweat gland carcinoma (EMPSGC), a low-grade sweat gland carcinoma with a predilection for the eyelids, often shows areas of benign eccrine cysts, atypical intracystic proliferation and associated mucinous carcinoma, suggesting tumor progression. Wilms tumor 1 (WT1) protein, a transcription factor, is overexpressed in many tumors and plays a role in oncogenesis. METHODS: A computer-based search for tumors diagnosed between 1989 and 2009 was conducted. Clinical data were obtained from pathology reports and patient records. Biopsies were reviewed for histologic features. Immunostaining was performed for WT1, chromogranin, synaptophysin, estrogen receptor (ER), epithelial membrane antigen (EMA), polyclonal carcinoembryonic antigen (P-CEA), cytokeratin 7 (CK7), cytokeratin 20 (CK20) and MIB-1. RESULTS: Eight women and five men (mean age: 61.2 years; range: 40-77 years) presented with slow-growing eyelid nodules. Cases of EMPSGC were characterized by the presence of dermal nodules with various growth patterns. Adjacent eccrine cysts were present in five patients, atypical epithelial proliferation within the cyst wall in four patients, and an associated mucinous carcinoma in one patient. All tumors were positive for WT1, CK7, ER, P-CEA and EMA and negative for CK20. Tumors were positive for synaptophysin in 12 cases and chromogranin in nine cases. The MIB-1 proliferation index was low in most cases. No WT1 staining was observed in the overlying epidermis, adnexal structures or areas of benign eccrine cyst. WT1 expression was observed in areas of atypical epithelial proliferation, and the neoplastic cells. CONCLUSIONS: The present study shows WT1 expression in the neoplastic epithelial cells of EMPSGC, areas of atypical intraductal proliferations, and mucinous carcinoma. The absence of WT1 expression in areas of benign eccrine cyst and cutaneous sweat glands suggests WT1 upregulation plays a role in tumor cell proliferation and progression of EMPSGC.
Kharbanda A, Rajabi H, Jin C, et al. Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells. Clin Cancer Res. 2014; 20(21):5423-34 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
PURPOSE: Non-small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known. EXPERIMENTAL DESIGN: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity. RESULTS: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC → AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK → ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK → ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants. CONCLUSIONS: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors.
Fend L, Gatard-Scheikl T, Kintz J, et al. Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control tumor growth upon combinatorial treatment with a TLR9 agonist. Cancer Immunol Res. 2014; 2(12):1163-74 [PubMed] Related Publications
Effector T-cell access to tumor tissue is a limiting step for clinical efficacy of antigen-specific T cell-based immunotherapies. Ectopic mouse tumor models, in which a subcutaneously (s.c.) implanted tumor is treated with s.c. or intramuscular therapeutic immunization, may not be optimal for targeting effector T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to evaluate the impact of injection routes on therapeutic efficacy of a Modified Vaccinia virus Ankara viral vector expressing the human mucin 1 tumor-associated xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of MVA-MUC1 displayed enhanced efficacy when compared with s.c. injection. Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9 agonist. In all cases, infiltration of tumor-bearing kidney by CD8(+) lymphocytes was associated with control of tumor growth. Biodistribution experiments indicate that, following i.v. injection, MVA-encoded antigens are quickly expressed in visceral organs and, in particular, in splenic antigen-presenting cells, compared with those following s.c. injection. This appears to result in a faster generation of MUC1-specific CD8(+) T cells. Lymphocytes infiltrating tumor-bearing kidneys are characterized by an effector memory phenotype and express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was associated with a modification of the tumor microenvironment toward a Th1-type immune response and recruitment of activated lymphocytes. This study supports the clinical evaluation of MVA-based immunotherapies via the i.v. route.
Li A, Zhou J, Lu H, et al. Pathological feature and immunoprofile of cystitis glandularis accompanied with upper urinary tract obstruction. Biomed Res Int. 2014; 2014:872170 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
OBJECTIVE: To explore the pathological feature and immunoprofile of immunoprofile accompanied with upper urinary tract obstruction and the immunoprofile in various types of glandular cystitis. METHODS: Pathological sections from 31 cases of cystitis glandularis with upper urinary tract obstruction and 34 cases of cystitis glandularis without upper urinary tract obstruction were observed as pathological feature on microscopy. Meanwhile, an immunohistochemical analysis was employed to determine the expression of p53, Ki67, p21, MMP-9, MUC1, MUC2, and COX-2. RESULTS: In the two groups, main pathological type was transitional epithelial, followed by intestinal epithelial; other types were a few, and the difference between the two groups was not significant. All immunohistochemical expressions of p53, Ki67, p21, MMP-9, MUC1, MUC2, and COX-2 were positive in varying degrees, and there was no significant difference between the groups. Transitional epithelial type was compared with mixed type; the difference of COX-2 was significant, P < 0.05. The differences of immunohistochemical expression among other different pathologic types were not significant. CONCLUSIONS: It is suggested that glandular cystitis accompanied with upper urinary tract obstruction shares the same pathological feature and immunoprofile as that without upper urinary tract obstruction. No significant differences of immunohistochemical expression in tissue are in cystitis glandularis with different pathological types.
Gheybi E, Amani J, Salmanian AH, et al. Designing a recombinant chimeric construct contain MUC1 and HER2 extracellular domain for prediagnostic breast cancer. Tumour Biol. 2014; 35(11):11489-97 [PubMed] Related Publications
Breast cancer is the most common cancer among women in the world. One of the approaches for diagnosis of breast cancer is detection of its tumor-associated markers. Mucin 1 (MUC1), a tumor-associated antigen, is a transmembrane glycoprotein expressed by normal epithelial cells and overexpressed by carcinomas of epithelial origin. Also, human epidermal growth factor receptor-2 (HER2/erbB-2) belongs to the one of four members of tyrosin kinase type 1 family in which overexpression of HER2 is associated with malignancy in breast cancer. This study was aimed to bioinformatics analysis and designing a recombinant chimeric protein containing MUC1 and HER2 antigens to express in prokaryotic host (Escherichia coli) as breast cancer diagnosis tools. The immunogenic sequences of MUC1 and HER2 were extracted and fused together by a linker. The chimeric construct was analyzed by bioinformatics softwares. The optimization and purification, evaluation of the expression of chimeric protein was performed using Western blotting, ELISA, and immunohistochemistry. The results showed that the chimeric construct was stable and immunogenic domains were exposed. The pET-28a vector containing chimeric gene had high level of protein expression. The recombinant chimeric protein was confirmed using Western blotting, and it was investigated using ELISA and IHC. Then, the MUC1 and HER2 combined peptides can be used as coating antigens in ELISA for detection of antibodies against MUC1 or HER2 in human serum.
Liszka L Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis. Pol J Pathol. 2014; 65(2):100-12 [PubMed] Related Publications
There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.
Miles WO, Korenjak M, Griffiths LM, et al. Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells. EMBO J. 2014; 33(19):2201-15 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE).
Xu X, Wells A, Padilla MT, et al. A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance. Carcinogenesis. 2014; 35(11):2457-66 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Acquired chemoresistance is a major challenge in cancer therapy. While the oncoprotein Mucin-1 (MUC1) performs multiple roles in the development of diverse human tumors, whether MUC1 is involved in acquired chemoresistance has not been determined. Using an acquired chemoresistance lung cancer cell model, we show that MUC1 expression was substantially increased in cells with acquired apoptosis resistance (AR). Knockdown of MUC1 expression effectively increased the sensitivity of these cells to the apoptotic cytotoxicity of anticancer therapeutics, suggesting that MUC1 contributes to acquired chemoresistance. Decreased catalase expression and increased cellular reactive oxygen species (ROS) accumulation were found to be associated with MUC1 overexpression. Scavenging ROS with butylated hydroxyanisole or supplying exogenous catalase dramatically suppressed MUC1 expression through destabilizing MUC1 protein, suggesting that reduced catalase expression mediated ROS accumulation is accounted for MUC1 overexpression. Further, we found that increased miR-551b expression in the AR cells inhibited the expression of catalase and potentiated ROS accumulation and MUC1 expression. Finally, by manipulating MUC1 expression, we found that MUC1 promotes EGFR-mediated activation of the cell survival cascade involving Akt/c-FLIP/COX-2 in order to protect cancer cells from responding to anticancer agents. Thus, our results establish a pathway consisting of miR-551b/catalase/ROS that results in MUC1 overexpression, and intervention against this pathway could be exploited to overcome acquired chemoresistance.
Kuhlmann JD, Wimberger P, Bankfalvi A, et al. ERCC1-positive circulating tumor cells in the blood of ovarian cancer patients as a predictive biomarker for platinum resistance. Clin Chem. 2014; 60(10):1282-9 [PubMed] Related Publications
BACKGROUND: Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance. METHODS: The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1. RESULTS: At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1(+)CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1(+)CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis. CONCLUSIONS: The presence of ERCC1(+)CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer.
Goschzik T, Gessi M, Denkhaus D, Pietsch T PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region. J Neuropathol Exp Neurol. 2014; 73(8):747-51 [PubMed] Related Publications
Papillary tumors of the pineal region (PTPR) are recognized as a distinct entity in the World Health Organization classification of CNS tumors. Papillary tumors of the pineal region frequently show loss of chromosome 10, but no studies have investigated possible target genes on this chromosome. Chromosome 10 harbors the PTEN (phosphatase and tensin homolog) gene, the inactivation of which, by mutation or epigenetic silencing, has been observed in different brain tumors, including high-grade gliomas. In this study, we investigated copy number changes by molecular inversion probe (MIP) analysis and the mutational status of PTEN in 13 PTPR by direct sequencing. MIP analysis of 5 PTPR showed chromosome 10 loss in all cases. In addition, there were losses of chromosomes 3, 14, 22, and X, and gains of whole chromosomes 8, 9, and 12 in more than 1 case. One case had a homozygous PTEN deletion; and 2 point mutations in exon 7 of PTEN (G251D and Q261stop) were found. Immunohistochemistry revealed decrease or loss of the PTEN protein and increased expression of p-Akt and p-S6. These results indicated that PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway may play a role in the biology of PTPR. This evidence may lead to the possible use of PI3K/Akt/mTOR inhibitors in therapy for patients with PTPR.
Abdelzaher E, Abdallah DM Expression of mesothelioma-related markers in meningiomas: an immunohistochemical study. Biomed Res Int. 2014; 2014:968794 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Meningiomas are common intracranial tumors. Recently, histogenetic and phenotypic similarities between meningiomas and mesotheliomas have been proposed. We were interested in whether these similarities are reflected on the immunohistochemical level, which would add new potentially diagnostic markers for meningiomas. METHODS: The expression of mesothelioma-related markers (D2-40, Calretinin, Keratin 5/6, WT1, and Methotheioma-Ab1) was investigated in 87 cases of meningiomas and compared to EMA expression. RESULTS: 73.6% of meningioma cases were grade I, 20.7% were grade II, and 5.7% were grade III. 83.9% of meningioma cases were classical and 16.1% had special nonmeningothelial features. D2-40 was expressed in 37.9% of cases and was significantly restricted to classical meningiomas. Calretinin and WT1 were negative while Keratin 5/6 and Mesothelioma-Ab1 were weakly expressed in classical variants (5.7% and 3.4%, resp.). EMA was consistently expressed in all cases. Its expression was significantly higher than that of mesothelioma-related markers; this held true also when D2-40 expression was considered separately. CONCLUSIONS: Mesothelioma-related markers are not extensively expressed in meningiomas, a finding that argues against their proposed histogenetic and phenotypic similarities. Compared to EMA, the significantly lower expression of mesothelioma-related markers and their restricted expression to classical meningioma variants hamper their potential future use as diagnostic markers for meningioma.
Sun Y, Gu J, Ajani JA, et al. Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: a case-control study. Cancer. 2014; 120(19):3040-8 [PubMed] Related Publications
BACKGROUND: Hispanics are the largest nonwhite ethnic group in the US population, and they have higher incidence and mortality rates for gastric cancer (GC) than whites and Asians. Studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for GC in whites and Asians. No studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics. METHODS: In a case-control study of 132 Hispanic patients with GC (cases) and a control group of 125 Hispanics (controls), the authors evaluated the association of 5 single nucleotide polymorphisms (SNPs) that predispose whites and/or Asians to GC and of 2 intermediate phenotypic markers in peripheral blood leukocytes, ie, telomere length and mitochondrial DNA (mtDNA) copy number, with the GC risk. RESULTS: The variant C allele of the reference SNP rs2294008 in the PSCA gene was associated with a significantly reduced risk of GC (per allele-adjusted odds ratio [aOR], 0.51; 95% confidence interval [CI], 0.33-0.77; P = .002). Leukocyte mtDNA copy numbers were significantly lower in GC cases (mean ± standard deviation, 0.91 ± 0.28) than in controls (1.29 ± 0.42; P < .001). When individuals were dichotomized into high and low mtDNA copy number groups based on the median mtDNA copy number value in the controls, those who had a low mtDNA copy number had a significantly increased risk of GC (aOR, 11.00; 95% CI, 4.79-25.23; P < .001) compared with those who had a high mtDNA copy number. Telomere length was not associated significantly with the risk of GC (aOR, 1.21; 95% CI, 0.65-2.27; P = .551). CONCLUSIONS: Hispanics share certain genetic susceptibility loci and intermediate phenotypic GC biomarkers with whites and Asians and may also have distinct genetic susceptibility factors.
Rudnicka H, Masojc B, van de Wetering T, et al. First recurrent large genomic rearrangement in the BRCA1 gene found in Poland. Cancer Epidemiol. 2014; 38(4):382-5 [PubMed] Related Publications
Mutation in the BRCA1 gene increases the risk of the person developing breast and/or ovarian cancer. The prevalence and spectrum of large genomic rearrangements (LGRs) varies considerably among different tested populations. In our previous study we described three LGRs in BRCA1 (exons 13-19, exon 17 and exon 22) in Polish families at high risk of breast and ovarian cancer. In this study we analyzed a group of 550 unselected women with ovarian cancer for the three previously identified LGRs. We used a rapid, single-step and closed-tube method: high-resolution melting analysis (HRMA). In this group of unrelated patients diagnosed with ovarian cancer we found three cases with the same deletions of exon 22. This is the first recurrent large deletion in BRCA1 found in Poland. We conclude that screening for the exon 22 deletion in BRCA1 should be included in the Polish BRCA1 genetic testing panel and possibly extended into other Slavic populations.
Mirecka A, Paszkowska-Szczur K, Scott RJ, et al. Common variants of xeroderma pigmentosum genes and prostate cancer risk. Gene. 2014; 546(2):156-61 [PubMed] Related Publications
The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA-XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR=2.60; p<0.001) and with the AA genotype (OR=531; p<0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer.
Deng M, Jing DD, Meng XJ Effect of MUC1 siRNA on drug resistance of gastric cancer cells to trastuzumab. Asian Pac J Cancer Prev. 2013; 14(1):127-31 [PubMed] Related Publications
Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.
Dai F, Zhang Y, Zhu X, et al. The anti-chemoresistant effect and mechanism of MUC1 aptamer-miR-29b chimera in ovarian cancer. Gynecol Oncol. 2013; 131(2):451-9 [PubMed] Related Publications
OBJECTIVE: Currently, there are no effective therapies for advanced ovarian cancer. In this study, we aim to determine the anti-tumor effect of MUC1 aptamer-miR-29b chimera in xenograft ovarian cancer models and chemo-resistance tumor model and to further explore the associated mechanism. METHODS: Xenograft ovarian cancer animal models were established using OVCAR-3, OVCA420, and OVCAR-3-Taxol cancer cells. The chimera (Chi-29b) was delivered through intraperitoneal injections. Tumor growth was evaluated. Gene expression and PTEN methylation were measured. RESULTS: We demonstrated that intratumoral injection of Chi-29b chimera significantly inhibited the growth of xenograft OVCAR-3 tumors through downregulating PTEN methylation, subsequent PTEN expression, as well as downregulating MAPK 4 and IGF1 expressions. In contrast, Chi-29b inhibited tumor growth in OVCA420 tumors by downregulating MAPK 4 & 10 and IGF1 expression without affecting PTEN expression. Intraperitoneal injection of Chi-29b significantly increased apoptosis in paclitaxel-resistant OVCAR-3 cells and inhibited the growth of xenograft OVCAR-3-Taxol tumors. The anti-chemoresistant role of Chi-29b in OVCAR-3-Taxol tumors was associated with the activation of PTEN signaling and downregulation of MAPK 4 and 10 and IGF1 expression. CONCLUSION: Our study indicated that Chi-29b chimera can effectively exert an anti-tumor effect in xenograft tumor models and an anti-chemoresistant role through inhibiting cancer stem cell activation.
Roulois D, Grégoire M, Fonteneau JF MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. Biomed Res Int. 2013; 2013:871936 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.
Sinn BV, von Minckwitz G, Denkert C, et al. Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2013; 24(9):2316-24 [PubMed] Related Publications
BACKGROUND: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015). CONCLUSIONS: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.
Nath S, Daneshvar K, Roy LD, et al. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes. Oncogenesis. 2013; 2:e51 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.
Suzuki Y, Sutoh M, Hatakeyama S, et al. MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis. Int J Oncol. 2012; 40(6):1831-8 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.
Swallow DM, Gendler S, Griffiths B, et al. The human tumour-associated epithelial mucins are coded by an expressed hypervariable gene locus PUM. Nature. 1987 Jul 2-8; 328(6125):82-4 [PubMed] Related Publications
A single highly-polymorphic autosomal gene locus PUM codes for a family of mucin-type glycoproteins, separable by SDS-gel electrophoresis, which we first identified in human urine. The locus also codes for glycoproteins which are abundant in several other normal epithelial tissues and body fluids, including milk, and in tumours of epithelial origin. These mucin-type glycoproteins seem to be very immunogenic in rodents and, in a search for epithelial specific or tumour-associated antigens, a large number of related antibodies have been isolated which bind to the PUM-coded mucins. Many of the antibodies show a pronounced tumour specificity on immunohistology and are being used widely in cancer diagnosis in vitro and in vivo and even in cancer therapy. To investigate the expression of these antigens in normal and malignant cells complementary DNA coding for the mammary mucin has been isolated. Here we present evidence obtained using this cDNA that the PUM locus is a hypervariable 'minisatellite' region of human DNA similar to those described by several groups, but which is novel in that it is transcribed and translated, and that the same polymorphism is demonstrable in the expressed gene product.
Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, et al. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem. 1990; 265(25):15286-93 [PubMed] Related Publications
Human mammary cells present on the cell surface a polymorphic epithelial mucin (PEM) which is developmentally regulated and aberrantly expressed in tumors. PEM carries tumor-associated epitopes recognized by the monoclonal antibodies HMFG-1, HMFG-2, and SM-3. Previously isolated partial cDNA clones revealed that the core protein contained a large domain consisting of variable numbers of 20-amino acid repeat units. We now report the full sequence for PEM, as deduced from cDNA sequences. The encoded protein consists of three distinct regions: the amino terminus consisting of a putative signal peptide and degenerate repeats; the major portion of the protein which is the tandem repeat region; the carboxyl terminus consisting of degenerate tandem repeats and a unique sequence containing a transmembrane sequence and a cytoplasmic tail. Potential O-glycosylation sites (serines or threonines) make up more than one-fourth of the amino acids. Length variations in the tandem repeat result in PEM being an expressed variable number tandem repeat locus. Tandem repeats appear to be a general characteristic of mucin core proteins.
Hirasawa Y, Kohno N, Yokoyama A, et al. Natural autoantibody to MUC1 is a prognostic indicator for non-small cell lung cancer. Am J Respir Crit Care Med. 2000; 161(2 Pt 1):589-94 [PubMed] Related Publications
A great deal of attention has been focused on the antitumor effects of anti-MUC1 humoral and cellular responses. We examined whether anti-MUC1 antibody is present in patients with lung cancer, and evaluated its prognostic value. Serum was obtained from 30 patients with nonresectable, non-small cell lung cancer (NSCLC) and 60 healthy volunteers. The presence of anti-MUC1 antibody was determined by enzyme-linked immunosorbent assay. The patients were observed for a median follow-up time of 54.0 mo. Overall survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed using the Cox proportional hazards regression model. Anti-KL-6/MUC1 antibody levels of the patients were significantly lower than those of normal individuals (p < 0.001). One-year survival rate of patients with high concentrations of anti-KL-6/MUC1 antibody was significantly higher than that of patients with low levels of anti-KL-6/MUC1 antibody (90.9% versus 21.1%, p < 0.001). Anti-KL-6/MUC1 antibody status was most strongly correlated with mortality, followed by lymph node status and albumin levels, whereas sex, serum lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA) levels, and metastasis status did not correlate with mortality. These preliminary results indicate that the degree of decrease in antibody level may be associated with a patient's prognosis.
Situ D, Wang J, Ma Y, et al. Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer. Med Oncol. 2011; 28 Suppl 1:S596-604 [PubMed] Related Publications
The goal of this study was to evaluate the expression of MUC1 in stage IB non-small cell lung cancer (NSCLC) and its prognostic significance. The expression of MUC1 in 178 NSCLC specimens was evaluated via immunohistochemistry. A reproducible semiquantitative method which took both staining percentage and intensity into account was applied for immunohistochemical scoring, and receiver operating characteristic curve analysis was utilized to select the cut-off score for high or low MUC1 expression. Then, the correlations between MUC1 expression and clinicopathological features and its prognostic relevance were determined. In this study, high MUC1 expression was detected more frequently in adenocarcinomas (86.3%) and other NSCLCs (74.1%) than in squamous cell carcinomas (39.1%, P < 0.001). The Kaplan-Meier survival curves showed that up-regulated expression of MUC1 indicated poorer overall survival (OS) and disease-free survival (DFS) (P = 0.011 and P = 0.008, respectively), especially for those with non-squamous cell carcinomas (P = 0.033 and P = 0.011, respectively). Multivariate analysis also confirmed that MUC1 expression was an independent prognostic factor for both OS and DFS in stage IB NSCLC (P = 0.008 and P = 0.004, respectively). MUC1 might be correlated with the histogenesis of lung adenocarcinoma, and its elevated expression may be an adverse prognostic indicator for the patients with stages IB NSCLC, particularly for those with non-squamous cell carcinomas.
Wei X, Xu H, Kufe D Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005; 7(2):167-78 [PubMed] Related Publications
The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas. The present work demonstrates that MUC1 associates with the p53 tumor suppressor, and that this interaction is increased by genotoxic stress. The MUC1 cytoplasmic domain binds directly to p53 regulatory domain. Chromatin immunoprecipitation assays demonstrate that MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. Conversely, MUC1 attenuates activation of Bax transcription. In concert with these results, MUC1 promotes selection of the p53-dependent growth arrest response and suppresses the p53-dependent apoptotic response to DNA damage. These findings indicate that MUC1 regulates p53-responsive genes and thereby cell fate in the genotoxic stress response.
Schroeder JA, Adriance MC, Thompson MC, et al. MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene. 2003; 22(9):1324-32 [PubMed] Related Publications
MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet its function as a tumor antigen is not fully understood. Recently, studies have shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and protein kinase Cdelta, possibly in a complex that promotes the disassembly of adherens junctions and the invasion of cells. Here we show that the deletion of Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild-type Muc1 background shows a tumor-specific complex formation between Muc1 and beta-catenin that can be observed in both the membrane and the cytoplasm of transformed epithelium. Analysis of primary human adenocarcinomas revealed that this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors, but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases their invasive capability, and these peptides colocalize with both beta-catenin and the focal adhesion protein vinculin, primarily at sites of membrane invasion into a collagen matrix. These data indicate a potential mechanism for MUC1 promotion of invasive tumorigenesis in the breast through the modulation of beta-catenin localization and subsequent cytoskeletal dynamics.
Dyomin VG, Palanisamy N, Lloyd KO, et al. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood. 2000; 95(8):2666-71 [PubMed] Related Publications
The band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cgamma) probe. The translocation linked the IGHG4 switch (Sgamma4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably, MUC1 transcription is aberrantly regulated by the IGHA (Calpha) 3' enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3' MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis. (Blood. 2000;95:2666-2671)
Gilles F, Goy A, Remache Y, et al. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood. 2000; 95(9):2930-6 [PubMed] Related Publications
Cytogenetic abnormalities at chromosome 1q21 are among the most common lesions in diffuse large-cell lymphoma and have been associated with a poor prognosis. A novel cell line, SKI-DLCL-1, was established from ascitic fluid that carries a t(1;14)(q21;q32) chromosomal translocation. Using pulsed-field gel electrophoresis, the breakpoint on the IgH locus mapped to a gamma locus between Calpha(1) and Calpha(2). A cosmid library was prepared from SKI-DLCL-1, and Cgamma-positive clones spanning the breakpoint were identified by screening with fluorescence in situ hybridization. The breakpoint occurs 860 bp downstream of the 3' UTR of the MUC1 gene. The break appears to be a staggered double-strand break consistent with an error in immunoglobulin class switching. The MUC1 gene is highly transcribed and translated, and the protein is highly glycosylated. It is postulated that MUC1 expression is brought under the control of the 3'Ealpha enhancer. MUC1 lies in a region of chromosome 1 characterized by an unusually high density of genes, with 7 known genes in a region of approximately 85 kb. To determine whether there was a pleiotropic effect of the expression of genes in the region as a consequence of the translocation, the expression of 6 additional genes was assessed. None of the other genes in this region (CLK2, propin, COTE1, GBA, metaxin, and thrombospondin 3) are overexpressed in SKI-DLCL-1. Thus, the translocation t(1;14)(q21;q32) seen in both the primary tumor and the derived cell line results in the marked overexpression of MUC1 without affecting the expression of other genes in the region. (Blood. 2000;95:2930-2936)
Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.
BACKGROUND: MUC1 and MUC3 are from a large family of glycoproteins with an aberrant expression profile in various malignancies. Much interest has been focused on the role of these proteins in the development and progression of colorectal cancer; however, no previous studies have included the highly confounding variable of vascular invasion in their survival analysis. Using high throughput tissue microarray technology we assessed the prognostic value of MUC1 and MUC3 expression in the largest cohort of colorectal cancer patients to date. We propose that tumours lacking expression of MUC1 and MUC3 will be more likely to metastasise, due to previously observed loss of cell-cell adhesion, and this will therefore lead to more aggressive cancers with poorer prognosis. METHODS: A tissue micro-array was prepared from tumour samples of 462 consecutive patients undergoing resection of a primary colorectal cancer. A comprehensive prospectively recorded data base with mean follow up of 75 months was collected and included common clinicopathological variables and disease specific survival. Immunohistochemical analysis of MUC1 and MUC3 expression was performed using antibodies NCL-MUC1 and 1143/B7 respectively, results were correlated with the variables within the database. RESULTS: Positive expression of MUC1 and MUC3 was seen in 32% and 74% of tumours respectively. On univariate analysis no correlation was seen with either MUC1 or MUC3 and any of the clinicopathological variables including tumour grade and stage, vascular invasion and tumour type. Kaplan-Meier analysis demonstrated a significant reduction in disease specific survival with MUC1 positive tumours (p = 0.038), this was not seen with MUC3 (p = 0.552). On multivariate analysis, using Cox proportional hazards model, MUC1 expression was shown to be an independent marker of prognosis (HR 1.339, 95%CI 1.002-1.790, p = 0.048). CONCLUSION: MUC1 expression in colorectal cancer is an independent marker of poor prognosis, even when vascular invasion is included in the analysis. These results support previous studies suggesting a role for MUC1 in colorectal cancer development possibly through its effects on cell adhesion.