KRT5

Gene Summary

Gene:KRT5; keratin 5
Aliases: K5, CK5, DDD, DDD1, EBS2, KRT5A
Location:12q13.13
Summary:The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:keratin, type II cytoskeletal 5
Source:NCBIAccessed: 10 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Breast Cancer
  • Young Adult
  • Trans-Activators
  • Biomarkers, Tumor
  • Receptors, Progesterone
  • Keratins
  • Lung Cancer
  • Mice, Transgenic
  • Bladder Cancer
  • Proportional Hazards Models
  • Keratin-5
  • Squamous Cell Carcinoma
  • Oligonucleotide Array Sequence Analysis
  • Immunohistochemistry
  • Skin
  • Receptor, erbB-2
  • Cancer Gene Expression Regulation
  • Nuclear Proteins
  • Gene Expression Profiling
  • Estrogen Receptors
  • Taiwan
  • Reproducibility of Results
  • Neoplasm Invasiveness
  • Pigmentation Disorders
  • Urothelium
  • Chromosome 12
  • Tumor Suppressor Proteins
  • Staging
  • Adenocarcinoma
  • Skin Cancer
  • Transfection
  • Cell Proliferation
  • Cell Differentiation
  • Phenotype
  • RTPCR
  • Ubiquitin-Protein Ligases
  • Promoter Regions
  • Keratin-6
  • Gene Expression
  • Messenger RNA
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KRT5 (cancer-related)

Dadhania V, Zhang M, Zhang L, et al.
Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use.
EBioMedicine. 2016; 12:105-117 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It has been suggested that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to chemotherapy. We aimed to validate these subtypes in several clinical cohorts and identify signature immunohistochemical markers that would permit simple and cost-effective classification of the disease in primary care centers.
METHODS: We analyzed genomic expression profiles of bladder cancer in three cohorts of fresh frozen tumor samples: MD Anderson (n=132), Lund (n=308), and The Cancer Genome Atlas (TCGA) (n=408) to validate the expression signatures of luminal and basal subtypes and relate them to clinical follow-up data. We also used an MD Anderson cohort of archival bladder tumor samples (n=89) and a parallel tissue microarray to identify immunohistochemical markers that permitted the molecular classification of bladder cancer.
FINDINGS: Bladder cancers could be assigned to two candidate intrinsic molecular subtypes referred to here as luminal and basal in all of the datasets analyzed. Luminal tumors were characterized by the expression signature similar to the intermediate/superficial layers of normal urothelium. They showed the upregulation of PPARγ target genes and the enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. In addition, luminal tumors were characterized by the overexpression of E-Cadherin, HER2/3, Rab-25, and Src. Basal tumors showed the expression signature similar to the basal layer of normal urothelium. They showed the upregulation of p63 target genes, the enrichment for TP53 and RB1 mutations, and overexpression of CD49, Cyclin B1, and EGFR. Survival analyses showed that the muscle-invasive basal bladder cancers were more aggressive when compared to luminal cancers. The immunohistochemical expressions of only two markers, luminal (GATA3) and basal (KRT5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy.
INTERPRETATION: The molecular subtypes of bladder cancer have distinct clinical behaviors and sensitivities to chemotherapy, and a simple two-marker immunohistochemical classifier can be used for prognostic and therapeutic stratification.
FUNDING: U.S. National Cancer Institute and National Institute of Health.

Tang P, Tse GM
Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update.
Arch Pathol Lab Med. 2016; 140(8):806-14 [PubMed] Related Publications
CONTEXT: -The pioneering works on molecular classification (MC) by Perou and Sorlie et al in the early 2000s using global gene expression profiling identified 5 intrinsic subtypes of invasive breast cancers (IBCs): luminal A, luminal B, normal breast-like, HER2-enriched, and basal-like subtypes, each unique in incidence, survival, and response to therapy. Because the application of gene expression profiling in daily practice is not economical or practical at the present time, many investigators have studied the use of immunohistochemical (IHC) surrogates as a substitute for determining the MC of IBC.
OBJECTIVE: -To discuss the continuing efforts that have been made to develop clinically significant and readily available IHC surrogates for the MC of IBC.
DATA SOURCES: -Data were obtained from pertinent peer-reviewed English-language literature.
CONCLUSIONS: -The most commonly used IHC surrogates are estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), dividing IBC into luminal, HER2, and triple-negative subtypes. The addition of Ki-67, cytokeratin 5, and epidermal growth factor receptor (EGFR) separates luminal B from luminal A subtypes, and basal-like subtype from triple-negative breast cancer. More recently, biomarkers such as androgen receptor and p53 have been shown to further stratify these molecular subtypes. Although many studies of IHC-based MC have shown clinical significance similar to gene expression profiling-defined MC, its critical limitations are: (1) a lack of standardization in terminology, (2) a lack of standardization in biomarkers used for each subtype, and (3) the lack of a uniform cutoff for each biomarker. A panel of IHC surrogates for each subtype of IBC is proposed.

Lesar M, Stanec M, Lesar N, et al.
IMMUNOHISTOCHEMICAL DIFFERENTIATION OF TRIPLE NEGATIVE BREAST CANCER.
Acta Clin Croat. 2016; 55(1):3-8 [PubMed] Related Publications
Based on immunohistochemical staining for the basal markers cytokeratin 5/6 (CK 5/6), cytokeratin 14 (CK 14) and P-cadherin, triple negative tumors (TNT) are divided into two groups: 1) basal-like (BL) positive for one or all three markers; and 2) non basal-like (NBL) negative for all three markers. Even though the different origin of the cells of these two types of tumors implies different biological properties, they had been treated as one entity until recently. This paper analyzes TNT collected from 150 patients and distributed into two groups according to the results of immunohistochemical analysis, i.e. BL 116 (77.3%) and NBL 34 (22.67%). In this study, CK 5/6, CK 14 and P-cadherin were used as markers for identifying BL tumors. The immunohistochemical reaction was positive for CK 5/6 in 37%, for CK 14 in 50.86% and for P-cadherin in 68.34% of cases. The subclassification of triple negative breast cancer using the basal markers CK 5/6, CK 14 and P-cadherin has enabled identification of BL and NBL breast cancers in a proportion that is in line with the only accurate analysis of TNT gene expression. Using the mentioned combination of markers in daily practice is easy to perform and economically affordable.

Zhang X, Li C, Wang D, et al.
Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma.
Gene. 2016; 590(2):285-92 [PubMed] Related Publications
Epigenetic modifications are critical determinants in tumor initiation and progression. This study aims to detect the promoter methylation status and the mRNA expression levels of ATG2B, ATG4D, ATG9A and ATG9B, and then to explore their relationship in invasive ductal carcinomas (IDCs) and matched normal tissues (MNTs) of the breast. Methylation was observed as follows: 61.0% in ATG2B, 46.8% in ATG4D, 56.4% in ATG9A, and 74.0% in ATG9B of IDCs. Meanwhile, their mRNA expression levels of the IDCs was lower than that of the MNTs (P<0.001, P=0.019, P<0.001 and P<0.001, respectively). Methylated IDCs of ATG2B, ATG9A, ATG9B and unmethylated ATG4D, ATG9B showed significantly lower expression values compared to the MNTs (P=0.003, P<0.001, P<0.001, P=0.014 and P=0.002, respectively). The methylations of ATG2B and ATG9B were related to their lower expression levels in IDCs (P=0.017 and P=0.023). Moreover, ATG2B methylation was positively associated with the grade (P=0.024) and TNM stage (P=0.015); Methylation of ATG4D and ATG9A was positively correlated to lymph node involvement (P=0.012 and P=0.018), while methylation of ATG9B appeared susceptible to CK5/6 positive status and deteriorated TNM stages (P=0.003 and P=0.012). Moreover, the decreased expression of ATG2B was related to the ER and PR status (P=0.004 and P=0.003). The ER, HER-2 and lymph node metastasis status are the determinants to reducing the expression of ATG4D, ATG9A and ATG9B (P=0.026, P=0.010 and P=0.011, respectively). This study highlights the transcriptional inactivation mechanisms of ATG2B, ATG4D, ATG9A and ATG9B promoter methylation status and the possible origin of autophagy signal pathway repression in IDCs.

Zhao W, Choi YL, Song JY, et al.
ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare.
Lung Cancer. 2016; 94:22-7 [PubMed] Related Publications
OBJECTIVES: Chromosomal rearrangements of ALK and ROS1 genes in non-small cell lung carcinoma (NSCLC) define a molecular subgroup of lung adenocarcinoma (ADC) that is amenable to targeted therapy with tyrosine kinase inhibitors (TKIs) crizotinib. Emerging clinical studies have demonstrated that patients with RET-rearranged NSCLC may also benefit from existing RET TKIs, including cabozantinib and vandetanib. However, the reported cases of lung squamous cell carcinomas (SCC) harboring gene rearrangements have been detected via fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) from materials such as biopsy or resection. Fusion events identified in lung SCC raise the question of whether this histologic subtype should also be evaluated for merit molecular testing. This work was undertaken to study the prevalence of lung SCC harboring ALK, ROS1, and RET translocations.
MATERIALS AND METHODS: Squamous cell carcinomas were confirmed using both histological examination by pathologists and immunohistochemistry analysis with positive staining of P63 and CK5/6 combined with negative CK7 and TTF-1 staining. 214 samples from surgically resected patient tissues were used to search for ALK, ROS1, and RET rearrangements by a NanoString analysis method. Fusion events were detected in a single-tube, multiplex assay system that relied on a complementary strategy of interrogation of 3' gene overexpression and detection of specific fusion transcript variants.
RESULTS AND CONCLUSION: ALK, ROS1 or RET gene rearrangements appeared 0 times out of 214 cases of lung SCC. Our data revealed that these fusions may be very rare in lung squamous cancer. The molecular screening strategy should therefore be focused on lung adenocarcinoma as the current National Comprehensive Cancer Network (NCCN) guideline recommends.

Tseng AW, Chen C, Breslin MB, Lan MS
Tumor-specific promoter-driven adenoviral therapy for insulinoma.
Cell Oncol (Dordr). 2016; 39(3):279-86 [PubMed] Related Publications
BACKGROUND: Insulinomas are the most common type of neuroendocrine (NE) pancreatic islet tumors. Patients with insulinomas may develop complications associated with hyperinsulinemia. To increase the treatment options for insulinoma patients, we have tested a conditionally replicating adenovirus that has been engineered in such a way that it can specifically express therapeutic genes in NE tumors.
METHODS: We used a promoter-specific adenoviral vector delivery system that is regulated by an INSM1 (insulinoma-associated-1) promoter, which is silent in normal adult tissues but active in developing NE cells and tumors. Through a series of modifications, using an insulator (HS4) and neuron-restrictive silencer elements (NRSEs), an oncolytic adenoviral vector was generated that retains tumor specificity and drives the expression of a mutated adenovirus E1A gene (Δ24E1A) and the herpes simplex virus thymidine kinase (HSV-tk) gene. The efficacy of this vector was tested in insulinoma-derived MIN, RIN, βTC-1 and pancreatic (Panc-1) cells using in vitro cell survival and in vivo tumor growth assays.
RESULTS: Using in vitro insulinoma-derived cell lines and an in vivo subcutaneous mouse tumor model we found that the INSM1 promoter-driven viruses were able to replicate specifically in INSM1-positive cells. INSM1-specific HSV-tk expression in combination with ganciclovir treatment resulted in dose-dependent tumor cell killing, leaving INSM1-negative cells unharmed. When we combined the INSM1-promoter driven HSV-tk with Δ24E1A and INSM1p-HSV-tk (K5) viruses, we found that the co-infected insulinoma-derived cells expressed higher levels of HSV-tk and exhibited more efficient tumor suppression than cells infected with INSM1p-HSV-tk virus alone.
CONCLUSIONS: INSM1 promoter-driven conditionally replicating adenoviruses may serve as a new tool for the treatment of insulinoma and may provide clinicians with additional options to combat this disease.

Gradiz R, Silva HC, Carvalho L, et al.
MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors.
Sci Rep. 2016; 6:21648 [PubMed] Free Access to Full Article Related Publications
Studies using cell lines should always characterize these cells to ensure that the results are not distorted by unexpected morphological or genetic changes possibly due to culture time or passage number. Thus, the aim of this study was to describe those MIA PaCa-2 and PANC-1 cell line phenotype and genotype characteristics that may play a crucial role in pancreatic cancer therapeutic assays, namely neuroendocrine chemotherapy and peptide receptor radionuclide therapy. Epithelial, mesenchymal, endocrine and stem cell marker characterization was performed by immunohistochemistry and flow cytometry, and genotyping by PCR, gene sequencing and capillary electrophoresis. MIA PaCa-2 (polymorphism) expresses CK5.6, AE1/AE3, E-cadherin, vimentin, chromogranin A, synaptophysin, SSTR2 and NTR1 but not CD56. PANC-1 (pleomorphism) expresses CK5.6, MNF-116, vimentin, chromogranin A, CD56 and SSTR2 but not E-cadherin, synaptophysin or NTR1. MIA PaCA-1 is CD24(-), CD44(+/++), CD326(-/+) and CD133/1(-), while PANC-1 is CD24(-/+), CD44(+), CD326(-/+) and CD133/1(-). Both cell lines have KRAS and TP53 mutations and homozygous deletions including the first 3 exons of CDKN2A/p16(INK4A), but no SMAD4/DPC4 mutations or microsatellite instability. Both have neuroendocrine differentiation and SSTR2 receptors, precisely the features making them suitable for the therapies we propose to assay in future studies.

Hirko KA, Willett WC, Hankinson SE, et al.
Healthy dietary patterns and risk of breast cancer by molecular subtype.
Breast Cancer Res Treat. 2016; 155(3):579-88 [PubMed] Free Access to Full Article Related Publications
We examined associations between dietary quality indices and breast cancer risk by molecular subtype among 100,643 women in the prospective Nurses' Health Study (NHS) cohort, followed from 1984 to 2006. Dietary quality scores for the Alternative Healthy Eating Index (AHEI), alternate Mediterranean diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns were calculated from semi-quantitative food frequency questionnaires collected every 2-4 years. Breast cancer molecular subtypes were defined according to estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor status from immunostained tumor microarrays in combination with histologic grade. Cox proportional hazards models, adjusted for age and breast cancer risk factors, were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Competing risk analyses were used to assess heterogeneity by subtype. We did not observe any significant associations between the AHEI or aMED dietary patterns and risk of breast cancer by molecular subtype. However, a significantly reduced risk of HER2-type breast cancer was observed among women in 5th versus 1st quintile of the DASH dietary pattern [n = 134 cases, Q5 vs. Q1 HR (95 % CI) = 0.44 (0.25-0.77)], and the inverse trend across quintiles was significant (p trend = 0.02). We did not observe any heterogeneity in associations between AHEI (p het = 0.25), aMED (p het = 0.71), and DASH (p het = 0.12) dietary patterns and breast cancer by subtype. Adherence to the AHEI, aMED, and DASH dietary patterns was not strongly associated with breast cancer molecular subtypes.

Johnson DT, Hooker E, Luong R, et al.
Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.
PLoS One. 2016; 11(2):e0148851 [PubMed] Free Access to Full Article Related Publications
Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Orzol P, Nekulova M, Holcakova J, et al.
ΔNp63 regulates cell proliferation, differentiation, adhesion, and migration in the BL2 subtype of basal-like breast cancer.
Tumour Biol. 2016; 37(8):10133-40 [PubMed] Related Publications
Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.

Nicol SM, Sabbah S, Brulois KF, et al.
Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells.
J Virol. 2016; 90(8):3849-59 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4(+)T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4(+)T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8(+)T cells, we suggest that CD4(+)T cells are potentially important effectors for thein vivocontrol of KSHV-infected B lymphocytes.
IMPORTANCE: KSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that recapitulates features seen in PEL and MCD by gene expression and cell phenotype analysis, allowing the study of T cell recognition of these cells. Challenge of KSHV-infected B cells with CD4(+)T cells specific for LANA, a protein expressed in all KSHV-infected cells and malignanciesin vivo, showed that these effectors could efficiently recognize such targets. Given that the virus expresses immune evasion genes or uses proteins with intrinsic properties, such as LANA, that minimize epitope recognition by CD8(+)T cells, CD4(+)T cell immunity to KSHV may be important for maintaining the virus-host balance.

Rekhi B, Joshi S, Panchwagh Y, et al.
Clinicopathological features of five unusual cases of intraosseous myoepithelial carcinomas, mimicking conventional primary bone tumours, including EWSR1 rearrangement in one case.
APMIS. 2016; 124(4):278-90 [PubMed] Related Publications
Primary intraosseous myoepithelial tumours, including carcinomas are rare tumours. The concept of histopathological spectrum of these tumours is evolving. We describe clinicopathological and immunohistochemical features of five myoepithelial carcinomas, including molecular cytogenetic results in one case. There were five male patients within age-range of 8-40 years (median = 26). Four tumours occurred in the long bones, including two tumours, each, in the femur and fibula, respectively, while a single tumour occurred in the proximal phalanges. Tumour size (n = 3 cases) varied from 5.6 to 8.6 cm. On radiological imaging, most tumours appeared as expansile, lytic and destructive lesions. Two tumours appeared as sclerotic lesions. Two cases were referred with diagnoses of chondrosarcomas and a single case was referred with two different diagnoses, including an adamantinoma and an osteosarcoma. Histopathological examination in all these cases showed multinodular tumours comprising mostly polygonal cells, exhibiting moderate nuclear atypia and interspersed mitotic figures within a stroma containing variable amount of myxoid, chondroid, hyalinised and osteoid-like material. Three tumours revealed prominent squamous differentiation. By immunohistochemistry, tumour cells were positive for EMA (5/5), pan CK (AE1/AE3) (3/3), CK5/6 (4/4), CK MNF116 (1/1), S100 protein (5/5) and GFAP (3/5). The first tumour revealed EWSR1 rearrangement. The first patient, 10 months after tumour resection and a simultaneous lung metastatectomy, is free-of-disease (FOD). The second patient, 11 months after tumour resection is FOD. The third and fourth patients underwent wide resections and are on follow-up. The fifth patient underwent resections, including a lung metastatectomy. Primary intraosseous myoepithelial carcinomas are rare and mimic conventional primary bone tumours. Some primary intraosseous myoepithelial carcinomas display EWSR1 rearrangement. Squamous differentiation may be considered as an addition to their evolving histopathological spectrum. Immunohistochemical stains constitute as a necessary tool for arriving at the correct diagnosis in such cases, which has treatment implications. Surgical resection remains the treatment mainstay.

Murria Estal R, Palanca Suela S, de Juan Jiménez I, et al.
Relationship of immunohistochemistry, copy number aberrations and epigenetic disorders with BRCAness pattern in hereditary and sporadic breast cancer.
Fam Cancer. 2016; 15(2):193-200 [PubMed] Related Publications
The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.

Kroiss M, Plonné D, Kendl S, et al.
Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma.
Eur J Endocrinol. 2016; 174(3):343-53 [PubMed] Related Publications
OBJECTIVE: Oral mitotane (o,p'-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC).
AIM: Serum mitotane concentrations >14  mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p'-dichlorodiphenylacetic acid (o,p'-DDA) and o,p'-dichlorodiphenyldichloroethane (o,p'-DDE).
DESIGN: Lipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI-H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins.
RESULTS: Chyle of the index patient contained 197  mg/ml mitotane, 53  mg/ml o,p'-DDA, and 51  mg/l o,p'-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction.
DISCUSSION: Mitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p'-DDE was similarly distributed, but 87.9±4.2% of o,p'-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI-H295 cells and reduced ER stress marker gene expression.
CONCLUSION: Mitotane absorption involves chylomicron binding. High concentrations of o,p'-DDA and o,p'-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.

Skowron MA, Niegisch G, Fritz G, et al.
Phenotype plasticity rather than repopulation from CD90/CK14+ cancer stem cells leads to cisplatin resistance of urothelial carcinoma cell lines.
J Exp Clin Cancer Res. 2015; 34:144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumour heterogeneity and resistance to systemic treatment in urothelial carcinoma (UC) may arise from cancer stem cells (CSC). A recent model describes cellular differentiation states within UC based on corresponding expression of surface markers (CD) and cytokeratins (CK) with CD90 and CK14 positive cells representing the least differentiated and most tumourigenic population. Based on the fact that this population is postulated to constitute CSCs and the origin of cisplatin resistance, we enriched urothelial carcinoma cell lines (UCCs) for CD90 and studied the tumour-initiating potential of these separated cells in vitro.
METHODS: Magnetic- and fluorescence-activated- cell sorting were used for separation of CD90(+) and CD90(-) UCCs. Distribution of cell surface markers CD90, CD44, and CD49f and cytokeratins CK14, CK5, and CK20 as well as the effects of short- and long-term treatment with cisplatin were assessed in vitro and measured by qRT-PCR, immunocytochemistry, reporter assay and flow cytometry in 11 UCCs.
RESULTS: We observed cell populations with surface markers according to those reported in tumour xenografts. However, expression of cytokeratins did not concord regularly with that of the surface markers. In particular, expression of CD90 and CK14 diverged during enrichment of CD90(+) cells by immunomagnetic sorting or following cisplatin treatment. Enriched CD90(+) cells did not exhibit CSC-like characteristics like enhanced clonogenicity and cisplatin resistance. Moreover, selection of cisplatin-resistant sublines by long-term drug treatment did not result in enrichment of CD90(+) cells. Rather, these sublines displayed significant phenotypic plasticity expressing EMT markers, an altered pattern of CKs, and WNT-pathway target genes.
CONCLUSIONS: Our findings indicate that the correspondence between CD surface markers and cytokeratins reported in xenografts is not maintained in commonly used UCCs and that CD90 may not be a stable marker of CSC in UC. Moreover, UCCs cells are capable of substantial phenotypic plasticity that may significantly contribute to the emergence of cisplatin resistance.

Shi S, Zhang M, Guo R, et al.
131I therapy mediated by sodium/iodide symporter combined with kringle 5 has a synergistic therapeutic effect on glioma.
Oncol Rep. 2016; 35(2):691-8 [PubMed] Related Publications
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor; the prognosis of patients with GBM remains poor. The sodium/iodide symporter (NIS) can be used to absorb several isotopes, such as 131I for nuclear medicine imaging and radionuclide therapy. Previously, we found that the early growth response-1 (Egr1) promoter had an 131I radiation positive feedback effect on the NIS gene. Kringle 5 (K5), a kringle domain of plasminogen, induced endothelial cell apoptosis. We investigated the effect of K5 combined with the 131I radiation positive feedback effect (Egr1-NIS) for treating malignant U87 glioma cells using a lentiviral vector. We successfully constructed a stable U87 glioma cell line, U87-K5-Egr1-NIS. The radio-inducible Egr1 promoter induced an 131I radiation positive feedback effect absorbed by NIS. Mediated by 131I, K5 increased glioma cell apoptosis; 131I radiation also increased endothelial cell sensitivity to K5-induced apoptosis. The combined therapy had a synergistic effect on the antitumor efficacy of glioma treatment, not only increasing tumor cell apoptosis but also significantly inhibiting tumor cell proliferation and reducing capillary density in U87 glioma tissues.

Madaras L, Balint N, Gyorffy B, et al.
BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters.
Pathobiology. 2016; 83(1):1-12 [PubMed] Related Publications
BACKGROUND: BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes.
METHODS: Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression.
RESULTS: In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively).
CONCLUSIONS: There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.

Kiselyov A, Bunimovich-Mendrazitsky S, Startsev V
Key signaling pathways in the muscle-invasive bladder carcinoma: Clinical markers for disease modeling and optimized treatment.
Int J Cancer. 2016; 138(11):2562-9 [PubMed] Related Publications
In this review, we evaluate key molecular pathways and markers of muscle-invasive bladder cancer (MIBC). Overexpression and activation of EGFR, p63, and EMT genes are suggestive of basal MIBC subtype generally responsive to chemotherapy. Alterations in PPARγ, ERBB2/3, and FGFR3 gene products and their signaling along with deregulated p53, cytokeratins KRT5/6/14 in combination with the cellular proliferation (Ki-67), and cell cycle markers (p16) indicate the need for more radical treatment protocols. Similarly, the "bell-shape" dynamics of Shh expression levels may suggest aggressive MIBC. A panel of diverse biological markers may be suitable for simulation studies of MIBC and development of an optimized treatment protocol. We conducted a critical evaluation of PubMed/Medline and SciFinder databases related to MIBC covering the period 2009-2015. The free-text search was extended by adding the following keywords and phrases: bladder cancer, metastatic, muscle-invasive, basal, luminal, epithelial-to-mesenchymal transition, cancer stem cell, mutations, immune response, signaling, biological markers, molecular markers, mathematical models, simulation, epigenetics, transmembrane, transcription factor, kinase, predictor, prognosis. The resulting selection of ca 500 abstracts was further analyzed in order to select the latest publications relevant to MIBC molecular markers of immediate clinical significance.

Liu WL, Wang LW, Chen JM, et al.
Application of multispectral imaging in quantitative immunohistochemistry study of breast cancer: a comparative study.
Tumour Biol. 2016; 37(4):5013-24 [PubMed] Free Access to Full Article Related Publications
Multispectral imaging (MSI) based on imaging and spectroscopy, as relatively novel to the field of histopathology, has been used in biomedical multidisciplinary researches. We analyzed and compared the utility of multispectral (MS) versus conventional red-green-blue (RGB) images for immunohistochemistry (IHC) staining to explore the advantages of MSI in clinical-pathological diagnosis. The MS images acquired of IHC-stained membranous marker human epidermal growth factor receptor 2 (HER2), cytoplasmic marker cytokeratin5/6 (CK5/6), and nuclear marker estrogen receptor (ER) have higher resolution, stronger contrast, and more accurate segmentation than the RGB images. The total signal optical density (OD) values for each biomarker were higher in MS images than in RGB images (all P < 0.05). Moreover, receiver operator characteristic (ROC) analysis revealed that a greater area under the curve (AUC), higher sensitivity, and specificity in evaluation of HER2 gene were achieved by MS images (AUC = 0.91, 89.1 %, 83.2 %) than RGB images (AUC = 0.87, 84.5, and 81.8 %). There was no significant difference between quantitative results of RGB images and clinico-pathological characteristics (P > 0.05). However, by quantifying MS images, the total signal OD values of HER2 positive expression were correlated with lymph node status and histological grades (P = 0.02 and 0.04). Additionally, the consistency test results indicated the inter-observer agreement was more robust in MS images for HER2 (inter-class correlation coefficient (ICC) = 0.95, r s = 0.94), CK5/6 (ICC = 0.90, r s = 0.88), and ER (ICC = 0.94, r s = 0.94) (all P < 0.001) than that in RGB images for HER2 (ICC = 0.91, r s = 0.89), CK5/6 (ICC = 0.85, r s = 0.84), and ER (ICC = 0.90, r s = 0.89) (all P < 0.001). Our results suggest that the application of MS images in quantitative IHC analysis could obtain higher accuracy, reliability, and more information of protein expression in relation to clinico-pathological characteristics versus conventional RGB images. It may become an optimal IHC digital imaging system used in quantitative pathology.

Fujii T, Shimada K, Tatsumi Y, et al.
microRNA-145 promotes differentiation in human urothelial carcinoma through down-regulation of syndecan-1.
BMC Cancer. 2015; 15:818 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A new molecular marker of carcinoma in the urinary bladder is needed as a diagnostic tool or as a therapeutic target. Potential markers include microRNAs (miRNAs), which are short, low molecular weight RNAs 19-24 nt long that regulate genes associated with cell proliferation, differentiation, and development in various cancers. In this study, we investigated the molecular mechanisms by which miR-145 promotes survival of urothelial carcinoma cells and differentiation into multiple lineages. We found miR-145 to regulate expression of syndecan-1, a heparin sulfate proteoglycan.
METHODS: Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7 was assessed by MTS assay. Cellular senescence and apoptosis were measured by senescence-associated β-galactosidase (SA-β-gal) and TUNEL assay, respectively. Quantitative RT-PCR was used to measure mRNA expression of various genes, including syndecan-1, stem cell factors, and markers of differentiation into squamous, glandular, or neuroendocrine cells.
RESULTS: Overexpression of miR-145 induced cell senescence, and thus significantly inhibited cell proliferation in T24 and KU7 cells. Syndecan-1 expression diminished, whereas stem cell markers such as SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated markers of differentiation into squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5 AC), and neuroendocrine cells (NSE and UCHL-1). Finally, expression of miR-145 was down-regulated in high-grade urothelial carcinomas, but not in low-grade tumors.
CONCLUSIONS: Results indicate that miR-145 suppresses syndecan-1 and, by this mechanism, up-regulates stem cell factors and induces cell senescence and differentiation. We propose that miR-145 may confer stem cell-like properties on urothelial carcinoma cells and thus facilitate differentiation into multiple cell types.

Boada LD, Henríquez-Hernández LA, Zumbado M, et al.
Organochlorine Pesticides Exposure and Bladder Cancer: Evaluation from a Gene-Environment Perspective in a Hospital-Based Case-Control Study in the Canary Islands (Spain).
J Agromedicine. 2016; 21(1):34-42 [PubMed] Related Publications
The incidence of bladder cancer has increased significantly since the 1950s. Pesticide exposure has been linked with increasing bladder cancer incidence, although the evidence is inconclusive. However, most epidemiological studies did not evaluate the potential role played by the organochlorine pesticides, the most widely used pesticides in Western countries from the 1940s to the 1970s. Organochlorine pesticides were banned in the late 1970s because of their persistence in the environment and their carcinogenic and mutagenic effects. Organochlorine pesticides were employed in huge amounts in the Spanish archipelago of the Canary Islands; the authors, therefore, evaluated the role played by organochlorine pesticides exposure on bladder cancer. Serum levels of the most prevalent organochlorine pesticides used in the agriculture of these Islands (dichlorodiphenyltrichloroethane [p,p'-DDT], and its metabolites dichlorodiphenyldichloroethylene [p,p'-DDE] and dichlorodiphenyldichloroethane [p,p'-DDD], hexachlorobenzene, hexachlorocyclohexane isomers, aldrin, dieldrin, endrin, heptachlor, cis-chlordane, trans-chlordane, α- and β-endosulfan, endosulfan sulfate, methoxychlor, and mirex) were measured in 140 bladder cancer cases and 206 controls. GST-M1 and GST-T1 gene polymorphisms were genotyped by polymerase chain reaction (PCR)-based methods. These results showed that serum levels of organochlorine pesticides did not increase bladder cancer risk. On the contrary, total burden of hexachlorocyclohexanes was found to be negatively associated to bladder cancer (odds ratio [OR] = 0.929, 95% confidence interval [CI]: 0.865-0.997; P = .041). This effect disappeared when the distribution of the gluthathione S-transferase polymorphisms was introduced in the statistical model. These results indicate that organochlorine pesticides are not a risk factor for bladder cancer. However, these findings provide additional evidence of gene-environment interactions for organochlorine pesticides and bladder cancer and reinforce the relevance of genes encoding xenobiotic-metabolizing enzymes in bladder cancer.

Yu KD, Jiang YZ, Hao S, Shao ZM
Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.
BMC Med. 2015; 13:254 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype.
METHODS: Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated.
RESULTS: Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy).
CONCLUSIONS: The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

Langbein L, Eckhart L, Fischer H, et al.
Localisation of keratin K78 in the basal layer and first suprabasal layers of stratified epithelia completes expression catalogue of type II keratins and provides new insights into sequential keratin expression.
Cell Tissue Res. 2016; 363(3):735-50 [PubMed] Related Publications
Among the 26 human type II keratins, K78 is the only one that has not yet been explored with regard to its expression characteristics. Here, we show that, at both the transcriptional and translational levels, K78 is strongly expressed in the basal and parabasal cell layers with decreasing intensity in the lower suprabasal cells of keratinising and non-keratinising squamous epithelia and keratinocyte cultures. The same pattern has been detected at the transcriptional level in the corresponding mouse epithelia. Murine K78 protein, which contains an extraordinary large extension of its tail domain, which is unique among all known keratins, is not detectable by the antibody used. Concomitant studies in human epithelia have confirmed K78 co-expression with the classical basal keratins K5 and K14. Similarly, K78 co-expression with the differentiation-related type I keratins K10 (epidermis) and K13 (non-keratinising epithelia) occurs in the parabasal cell layer, whereas that of the corresponding type II keratins K1 (epidermis) and K4 (non-keratinising epithelia) unequivocally starts subsequent to the respective type I keratins. Our data concerning K78 expression modify the classical concept of keratin pair K5/K14 representing the basal compartment and keratin pairs K1/K10 or K4/K13 defining the differentiating compartment of stratified epithelia. Moreover, the K78 expression pattern and the decoupled K1/K10 and K4/K13 expression define the existence of a hitherto unperceived early differentiation stage in the parabasal layer characterized by K78/K10 or K78/K13 expression.

Guo W, Wang W, Zhu Y, et al.
HER2 status in molecular apocrine breast cancer: associations with clinical, pathological, and molecular features.
Int J Clin Exp Pathol. 2015; 8(7):8008-17 [PubMed] Free Access to Full Article Related Publications
Molecular apocrine breast cancer (MABC) is a distinct subtype of breast cancer. The purpose of this study was to investigate the relationship between HER2 status and clinicopathologic characteristics of MABCs from Chinese Han cohort. A cohort of 90 MABC patients were enrolled. Immunohistochemical method was performed to analyze the molecular expression, and the human epidermal growth factor receptor 2 (HER2) amplification was verified by fluorescence in situ hybridization (FISH). By studying these 90 MABC cases, the majority of studied patients were premenopausal young women (median age 48 yr) with high grade tumors. We also found that MABCs had high positive expression rates of HER2, CK8, CD44, CD166, p53 and BRCA1, the elevated Ki-67 labeling index, and favorable prognosis. There was a significantly higher incidence of lymph node metastasis and lower CD166 positive rate in HER2-negative patients compared to HER2-positive patients (54.5% vs. 37.0%, P = 0.044 and 72.7% vs. 91.3%, P = 0.021, respectively). The CK5/6 and EGFR expression rates were significant higher in HER2-negative cases than in HER2-positive cases, suggesting that there is overlap between MABC with HER2-negative phenotype and basal-like breast cancer. In addition, HER2 positive was found to be significantly associated a poor overall survival in MABCs. In conclusion, HER2 are highly expressed, and HER2 positivity could be considered as a significant biomarker of poor prognosis in MABC. The results also suggest that a subtype tumor with distinct patterns of molecule expression depending on HER2 status presented in MABC.

Pickup MW, Hover LD, Guo Y, et al.
Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis.
Oncotarget. 2015; 6(26):22890-904 [PubMed] Free Access to Full Article Related Publications
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) family. BMP ligands have been shown to be overexpressed in human breast cancers. Normal and cancerous breast tissue display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyMT oncogene with mice having conditional knockout (cKO) of BMP receptor type 1a (BMPR1a) using whey acidic protein (WAP)-Cre and found this deletion resulted in delayed tumor onset and significantly extended survival. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicates that epithelial-to-mesenchymal (EMT)-like transitions occurred in cKO tumors. We performed microarray analysis on these tumors and found changes that support EMT-like changes. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and in vivo upon implantation. cKO tumor cells had reduced migration in vitro. We analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions, and found that high BMPR1a gene expression correlates with decreased survival regardless of molecular breast cancer subtype. In conclusion, the data indicate that BMP signaling through BMPR1a functions as a tumor promoter.

Vranic S, Marchiò C, Castellano I, et al.
Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast.
Hum Pathol. 2015; 46(9):1350-9 [PubMed] Related Publications
Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity [Ki-67, phosphohistone H3], infrequent (~10%) expression of basal cell markers [CK5/6, CK14, p63, caveolin-1], loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC, CCND1, ZNF703, CDH1, and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH (κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2-positive and HER2-negative (P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the "luminal-complex" phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations.

Dahlhoff M, Schäfer M, Muzumdar S, et al.
ERBB3 is required for tumor promotion in a mouse model of skin carcinogenesis.
Mol Oncol. 2015; 9(9):1825-33 [PubMed] Related Publications
The epidermal growth factor receptor (EGFR) plays a key role in skin inflammation, wound healing, and carcinogenesis. Less is known about the functions of the structurally related receptor ERBB3 (HER3) in the skin. We assessed the requirement of ERBB3 for skin homeostasis, wound healing, and tumorigenesis by crossing mice carrying a conditional Erbb3 allele with animals expressing cre under the control of the keratin 5 promoter. Erbb3(del) mice, lacking ERBB3 specifically in keratinocytes, showed no obvious abnormalities. The EGFR was upregulated in Erbb3(del) skin, possibly compensating the loss of ERBB3. Nonetheless, healing of full-thickness excisional wounds was negatively affected by ERBB3 deficiency. To analyze the function of ERBB3 during tumorigenesis, we employed the established DMBA/TPA multi-stage chemical carcinogenesis protocol. Erbb3(del) mice remained free of papillomas for a longer time and had significantly reduced tumor burden compared to control littermates. Tumor cell proliferation was considerably reduced in Erbb3(del) mice, and loss of ERBB3 also impaired keratinocyte proliferation after a single application of TPA. In human skin tumor samples, upregulated ERBB3 expression was observed in squamous cell carcinoma, condyloma, and malignant melanoma. Thus, we conclude that ERBB3, while dispensable for the development and the homeostasis of the epidermis and its appendages, is required for proper wound healing and for the progression of skin tumors during multi-stage chemical carcinogenesis in mice. ERBB3 may also be important for human skin cancer progression. The latter effects most probably reflect a key role for ERBB3 in increasing cell proliferation after stimuli as wounding or carcinogenesis.

Rampisela D, Zreik R, Donner LR
Thymic Tumor With Adenoid Cystic Carcinoma-Like Features: A Study of a Clinically Favorable Case Followed for 9 Years.
Int J Surg Pathol. 2015; 23(7):557-60 [PubMed] Related Publications
Thymic tumors with adenoid cystic carcinoma-like features are true rarities, with only 6 cases reported. Our knowledge of their clinical behavior is insufficient. We present a case of a noninvasive cribriform tumor that was followed, including a 4-year period after tumor resection and radiation therapy, for a total of 9 years. The tumor was purely epithelial. It was positive for keratins (AE-1/AE-3, CK19, 34βE12,CK5/6), MOC-31, P63, P40, CD10, and MYB, and was negative for myoepithelial or neuroendocrine markers. Presence of cell processes, desmosome-like junctions with tonofilaments and multifocally reduplicated basal lamina was noted on ultrastructural examination. Two signals of the MYB gene per cell were detected by fluorescence in situ hybridization. No monosomy or translocations of the gene were found. Although additional clinical studies are necessary, it seems that indolent behavior of cribriform noninvasive subset of these tumors may be anticipated.

Sobral-Leite M, Wesseling J, Smit VT, et al.
Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis.
BMC Med. 2015; 13:156 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients.
METHODS: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model.
RESULTS: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45).
CONCLUSIONS: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.

Karlsson A, Brunnström H, Lindquist KE, et al.
Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.
Oncotarget. 2015; 6(26):22028-37 [PubMed] Free Access to Full Article Related Publications
Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.

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