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S100A6; S100 calcium binding protein A6 (1q21)

Gene Summary

Gene:S100A6; S100 calcium binding protein A6
Aliases: 2A9, PRA, 5B10, CABP, CACY
Location:1q21
Summary:The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-dependent insulin release, stimulation of prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of this gene have been implicated in melanoma. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein S100-A6
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 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.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (6)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
MelanomaS100A6 Expression in Melanoma View Publications16
Brain and CNS TumoursS100A6 Expression in CNS Tumors View Publications10
Soft Tissue SarcomaS100A6 and Soft Tissue Sarcoma View Publications6
Liver CancerS100A6 and Liver Cancer View Publications6
Stomach CancerS100A6 and Stomach Cancer View Publications6
Pancreatic CancerS100A6 and Pancreatic Cancer View Publications6

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

Related Links

Latest Publications: S100A6 (cancer-related)

Zhang J, Zhang K, Jiang X, Zhang J
S100A6 as a potential serum prognostic biomarker and therapeutic target in gastric cancer.
Dig Dis Sci. 2014; 59(9):2136-44 [PubMed] Related Publications
BACKGROUND: Increased expression of S100A6 in many cancer tissues and its association with tumor behavior and patient prognosis were demonstrated, and there are no studies analyzing the serum levels of S100A6 in patients with gastric cancer (GC).
AIM: Serum S100A6 levels were investigated as a marker of tumor aggressiveness in patients with GC, and the S100A6 gene was examined as a potential therapeutic target in GC.
METHODS: Serum S100A6 levels were detected in 103 GC patients and 72 healthy subjects by ELISA. Clinicopathological features of GC patients were analyzed in correlation to serum S100A6 levels. Two small interfering RNAs against S100A6 (siRNA1-S100A6 and siRNA2-S100A6) were generated and transfected into SGC7901 cells using pSUPER gfp-neo vector, and the effects of S100A6 knockdown on cell proliferation, invasion and apoptosis were evaluated in vitro. The effects of S100A6 silencing on tumor growth and metastasis were evaluated in vivo in a pseudo-metastatic GC nude mouse model.
RESULTS: Serum S100A6 levels were significantly higher in GC patients than in healthy controls (P < 0.001). Serum S100A6 levels were significantly correlated with lymph node metastasis, TNM stage, perineural invasion and vascular invasion. Serum S100A6 level was an independent predictor of overall survival. SiRNA-mediated silencing of S100A6 significantly induced apoptosis and decreased proliferation, clone formation and the invasiveness of GC SGC7901 cells in vitro and significantly reduced tumor volume and number in vivo (P < 0.01).
CONCLUSION: Serum S100A6 level may serve as a potential prognostic biomarker in GC. Inhibition of S100A6 decreased the metastatic potential of GC cells.

Related: Apoptosis Stomach Cancer Gastric Cancer


Duan L, Wu R, Zou Z, et al.
S100A6 stimulates proliferation and migration of colorectal carcinoma cells through activation of the MAPK pathways.
Int J Oncol. 2014; 44(3):781-90 [PubMed] Related Publications
The S100A6 protein, a member of the S100 protein family, is overexpressed in many tumors including colorectal carcinoma (CRC). Although recent studies showed that the elevated expression of S100A6 was associated with the stage and lymphatic permeation of CRC, little is known about whether and how S100A6 contributes to CRC development. Here we investigated the S100A6 expression in CRC tissues and cell lines, and explored the molecular mechanisms underlying the role of S100A6 in CRC development by examining cell proliferation and migration in vitro, and tumorigenicity in nude mice. The results show that S100A6 expression was markedly increased in CRC tissues and cell lines compared to normal colon tissues and a normal colon mucosal epithelial cell line, respectively. Recombinant adenovirus-mediated overexpression of S100A6 or treatment with recombinant S100A6 protein in HCT116, a CRC cell line with relative low S100A6 expression, resulted in enhanced cell proliferation and migration, and the mitogen-activated protein kinase (MAPK) activation in vitro, and tumor growth in vivo. Conversely, RNAi-mediated knockdown of S100A6 in LoVo, a CRC cell line with relative high S100A6 expression, resulted in reduced cell proliferation, migration and MAPK activity. S100A6-induced proliferation was partially attenuated by an ERK inhibitor while migration was suppressed by a p38 inhibitor. Taken together, our results suggest that the cellular effects of S100A6 are mediated by the ERK and p38 MAPK pathways, and modulation of these pathways may be employed for CRC prevention and therapy.

Related: Colorectal (Bowel) Cancer


Li Z, Tang M, Ling B, et al.
Increased expression of S100A6 promotes cell proliferation and migration in human hepatocellular carcinoma.
J Mol Med (Berl). 2014; 92(3):291-303 [PubMed] Related Publications
UNLABELLED: High levels of S100A6 have been associated with poor outcome in some types of human cancers, but the role of S100A6 in the molecular pathogenesis of these cancers is largely unknown. This study was performed to explore the expression and functional roles of S100A6 in hepatocellular carcinoma (HCC). The expression level of S100A6 in HCC tumor and corresponding peritumoral tissues were determined by immunohistochemistry analysis. The potential functions of S100A6 in tumorigenesis and metastasis were analyzed by cell proliferation, migration, and invasion assays in human liver cancer cells. Moreover, through expression and purification of S100A6 recombinant protein tagged with cell-penetrating peptide, we analyzed its complex extracellular/intracellular effects in a S100A6-silenced cellular model. As a result, the expression of S100A6 was up-regulated in human HCC compared with adjacent peritumoral tissues. S100A6 silencing inhibited the growth and motility of HCC cells, while intracellular re-expression of S100A6 could rescue the proliferation and migration defects. Intracellular over-expression of S100A6 resulted in down-regulation of E-cadherin expression and promoted nuclear accumulation of β-catenin. Moreover, we found that the enhanced cell proliferation and motility after S100A6 stimulation were dependent on the activation of PI3K/AKT pathway. These results suggest that S100A6 may be involved in promotion and progression of human liver cancer.
KEY MESSAGES: S100A6 is overexpressed in human hepatocellular carcinoma clinical specimens. S100A6 promotes proliferation and migration of human hepatoma cells. Overexpression of S100A6 results in alteration of E-cadherin and β-catenin. The multi-effects of S100A6 may be mediated in part by PI3K/AKT pathway activation.

Related: Liver Cancer AKT1 Signal Transduction CTNNB1 gene


Kariagina A, Xie J, Langohr IM, et al.
Progesterone stimulates proliferation and promotes cytoplasmic localization of the cell cycle inhibitor p27 in steroid receptor positive breast cancers.
Horm Cancer. 2013; 4(6):381-90 [PubMed] Related Publications
Progestins are reported to increase the risk of more aggressive estrogen receptor positive, progesterone receptor positive (ER+ PR+) breast cancers in postmenopausal women. Using an in vivo rat model of ER+ PR + mammary cancer, we show that tumors arising in the presence of estrogen and progesterone exhibit increased proliferation and decreased nuclear expression of the cell cycle inhibitor p27 compared with tumors growing in the presence of estrogen alone. In human T47D breast cancer cells, progestin increased proliferation and decreased nuclear p27 expression. The decrease of nuclear p27 protein was dependent on activation of Src and PI3K by progesterone receptor isoforms PRA or PRB. Importantly, increased proliferation and decreased nuclear p27 expression were observed in invasive breast carcinoma compared with carcinoma in situ. These results suggest that progesterone specifically regulates intracellular localization of p27 protein and proliferation. Therefore, progesterone-activated pathways can provide useful therapeutic targets for treatment of more aggressive ER+ PR+ breast cancers.

Related: Breast Cancer CDKN1A


Yu Y, Liu L, Xie N, et al.
Expression and function of the progesterone receptor in human prostate stroma provide novel insights to cell proliferation control.
J Clin Endocrinol Metab. 2013; 98(7):2887-96 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Like other tissues, the prostate is an admixture of many different cell types that can be segregated into components of the epithelium or stroma. Reciprocal interactions between these 2 types of cells are critical for maintaining prostate homeostasis, whereas aberrant stromal cell proliferation can disrupt this balance and result in diseases such as benign prostatic hyperplasia. Although the androgen and estrogen receptors are relatively well studied for their functions in controlling stromal cell proliferation and differentiation, the role of the progesterone receptor (PR) remains unclear.
OBJECTIVE: The aim of the study was to investigate the expression and function of the PR in the prostate.
DESIGN AND SETTING: Human prostate biopsies, renal capsule xenografts, and prostate stromal cells were used. Immunohistochemistry, Western blotting, real-time quantitative PCR, cell proliferation, flow cytometry, and gene microarray analyses were performed.
RESULTS: Two PR isoforms, PRA and PRB, are expressed in prostate stromal fibroblasts and smooth muscle cells, but not in epithelial cells. Both PR isoforms suppress prostate stromal cell proliferation through inhibition of the expression of cyclinA, cyclinB, and cdc25c, thus delaying cell cycling through S and M phases. Gene microarray analyses further demonstrated that PRA and PRB regulated different transcriptomes. However, one of the major gene groups commonly regulated by both PR isoforms was the one associated with regulation of cell proliferation.
CONCLUSION: PR plays an inhibitory role in prostate stromal cell proliferation.

Related: Prostate Cancer


Bellance C, Khan JA, Meduri G, et al.
Progesterone receptor isoforms PRA and PRB differentially contribute to breast cancer cell migration through interaction with focal adhesion kinase complexes.
Mol Biol Cell. 2013; 24(9):1363-74 [PubMed] Free Access to Full Article Related Publications
Progesterone receptor (PR) and progestins affect mammary tumorigenesis; however, the relative contributions of PR isoforms A and B (PRA and PRB, respectively) in cancer cell migration remains elusive. By using a bi-inducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the effect of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(-) cells. 17,21-Dimethyl-19-norpregna-4,9-dien-3,20-dione (R5020) progestin limited this effect and was counteracted by the antagonist 11β-(4-dimethyl-amino)-phenyl-17β-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one (RU486). Of importance, PRA coexpression potentiated PRB-mediated migration, whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration, such as urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor type 1, uPA receptor (uPAR), and β1-integrin, which affect focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation and colocalized with activated FAK in cell protrusions. Because PRB, as well as PRA, coimmunoprecipitated with FAK, both isoforms can interact with FAK complexes, depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such an effect of PRB/PRA expression on FAK signaling might thus affect adhesion/motility, underscoring the implication of PR isoforms in breast cancer invasiveness and metastatic evolution with underlying therapeutic outcomes.

Related: Breast Cancer


Patel AR, Chougule MB, I T, et al.
Efficacy of aerosolized celecoxib encapsulated nanostructured lipid carrier in non-small cell lung cancer in combination with docetaxel.
Pharm Res. 2013; 30(5):1435-46 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Evaluation of in-vivo anticancer activity of aerosolized Celecoxib encapsulated Nanolipidcarriers (Cxb-NLC) as a single therapeutic agent and combined with intravenously administered Docetaxel (Doc) against non-small cell lung cancer.
METHODS: Cxb-NLC were prepared by high-pressure homogenization and were characterized for its physicochemical characteristics. Metastatic A549 tumor model in Nu/Nu mice was used to evaluate response of aerosolized Cxb-NLC & Doc. Isolated lung tumor samples were analyzed for: a) DNA fragmentation and cleaved caspase-3 by immunohistochemistry, b) apoptotic and angiogenic protein markers by western blot, c) global proteomic alterations by an isobaric labeling quantitative proteomic method and d) toxicity studies of NLC.
RESULTS: The particle size of Cxb-NLC was 217 ± 20 nm, while entrapment efficiency was more than 90%. Cxb-NLC and Doc alone and in combination showed 25 ± 4%, 37 ± 5%, and 67 ± 4% reduction in tumor size respectively compared to control. Proteomic analysis with combination treatment further revealed significantly decreased expression of multiple pro-survival and pro-metastasis proteins as well as tumor invasion markers and the expression of S100 family proteins, such as S100A6 and S100P were decreased by 2.5 and 1.6 fold.
CONCLUSIONS: Combination therapy with Cxb-NLC and Doc showed significant reduction in tumor growth which was further confirmed by proteomic analysis.

Related: Non-Small Cell Lung Cancer Lung Cancer Docetaxel


Wang L, Shi J, Zhang H, et al.
Synergistic anticancer effect of RNAi and photothermal therapy mediated by functionalized single-walled carbon nanotubes.
Biomaterials. 2013; 34(1):262-74 [PubMed] Related Publications
Single-walled carbon nanotubes (SWNTs) are special nano-materials which exhibit interesting physical and chemical properties, presenting new opportunities for biomedical research and applications. In this study, we have successfully adopted a novel strategy to chemically functionalize SWNTs with polyethylenimine (PEI) through purification, oxidation, amination and polymerization, which were then bound by DSPE-PEG2000-Maleimide for further conjugation with the tumor targeting NGR (Cys-Asn-Gly-Arg-Cys-) peptide via the maleimide group and sulfhydryl group of cysteine, and finally hTERT siRNA was loaded to obtain a novel tumor targeting siRNA delivery system, designated as SWNT-PEI/siRNA/NGR. The results showed that SWNT-PEI/siRNA/NGR could efficiently cross cell membrane, induced more severe apoptosis and stronger suppression in proliferation of PC-3 cells in vitro. Furthermore, in tumor-bearing mice model the delivery system exhibited higher antitumor activity due to more accumulation in tumor without obvious toxicity in main organs. The combination of RNAi and near-infrared (NIR) photothermal therapy significantly enhanced the therapeutic efficacy. In conclusion, SWNT-PEI/siRNA/NGR is a novel and promising anticancer system by combining gene therapy and photothermal therapy.

Related: Apoptosis Cancer Prevention and Risk Reduction


Khan JA, Bellance C, Guiochon-Mantel A, et al.
Differential regulation of breast cancer-associated genes by progesterone receptor isoforms PRA and PRB in a new bi-inducible breast cancer cell line.
PLoS One. 2012; 7(9):e45993 [PubMed] Free Access to Full Article Related Publications
Progesterone receptor isoforms (PRA and PRB) are expressed at equal levels in normal mammary cells. However, alteration in PRA/PRB expression is often observed in aggressive breast cancer suggesting differential contribution of PR isoforms in carcinogenesis. The mechanisms underlying such processes remain to be established mainly due to paucity of appropriate cellular models. To investigate the role of PR isoforms and the impact of imbalanced PRA/PRB ratio in transcriptional regulation, we have generated an original human breast cancer cell line conditionally expressing PRA and/or PRB in dose-dependence of non-steroid inducers. We first focused on PR-dependent transcriptional regulation of the paracrine growth factor gene amphiregulin (AREG) playing important role in cancer. Interestingly, unliganded PRA increases AREG expression, independently of estrogen receptor, yet inhibitable by antiprogestins. We show that functional outcome of epidermal growth factor (EGF) on such regulation is highly dependent on PRA/PRB ratio. Using this valuable model, genome-wide transcriptomic studies allowed us to determine the differential effects of PRA and PRB as a function of hormonal status. We identified a large number of novel PR-regulated genes notably implicated in breast cancer and metastasis and demonstrated that imbalanced PRA/PRB ratio strongly impact their expression predicting poor outcome in breast cancer. In sum, our unique cell-based system strongly suggests that PRA/PRB ratio is a critical determinant of PR target gene selectivity and responses to hormonal/growth factor stimuli. These findings provide molecular support for the aggressive phenotype of breast cancers with impaired expression of PRA or PRB.

Related: Breast Cancer


Cao CX, Yang XC, Gao YX, et al.
Expression of aldosterone synthase and adrenocorticotropic hormone receptor in adrenal incidentalomas from normotensive and hypertensive patients: Distinguishing subclinical or atypical primary aldosteronism from adrenal incidentaloma.
Int J Mol Med. 2012; 30(6):1396-402 [PubMed] Related Publications
The present study aimed to investigate the expression of aldosterone synthase (CYP11B2), adrenocorticotropic hormone receptor (ACTH-R) and their regulating transcription factors in adrenal incidentalomas (AIs) from normotensive and hypertensive patients to distinguish subclinical or atypical primary aldosteronism (PA) from AIs. Total RNA was extracted from 8 normal adrenal cortices (NAs), 46 AIs, 15 aldosterone-producing adenomas (APAs) and 6 idiopathic hyperaldosteronisms (IHAs). Real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry were performed to determine the mRNA and protein expression of CYP11B2, ACTH-R, steroidogenic factor-1 (SF1) and dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1 (DAX-1) in the different tissues. The AI hypertensive subgroup displayed increased plasma aldosterone concentration (PAC) and PAC/PRA ratio (ARR) and decreased plasma renin activity (PRA) compared to the normotensive group. CYP11B2, ACTH-R and SF1 mRNAs were significantly higher in the APA group compared to the other groups, and gradually increased in AI hypertensive samples. DAX-1 mRNA was expressed faintly in PA compared with NA. In normotensive-AI samples, DAX-1 mRNA was higher compared to PA and AI hypertensive samples. Significant differences in gene expression levels in AIs were observed between probable and improbable PA patients. Immunohistochemical results were consistent with those of real-time PCR. Plasma aldosterone levels were positively correlated with CYP11B2, ACTH-R and SF1 mRNA and inversely correlated with DAX-1 mRNA. In conclusion, a significant number of hypertensive-AI patients may have subclinical forms of PA. CYP11B2, ACTH-R and their regulating transcription factors may be noteworthy in distinguishing subclinical PA from AIs.


Barry S, Chelala C, Lines K, et al.
S100P is a metastasis-associated gene that facilitates transendothelial migration of pancreatic cancer cells.
Clin Exp Metastasis. 2013; 30(3):251-64 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is the 5th most common cause of cancer death in the UK and the 4th in the US. The vast majority of deaths following pancreatic cancer are due to metastatic spread, hence understanding the metastatic process is vital for identification of critically needed novel therapeutic targets. An enriched set of 33 genes differentially expressed in common between primary PDAC and liver metastases, when compared to normal tissues, was obtained through global gene expression profiling. This metastasis-associated gene set comprises transcripts from both cancer (S100P, S100A6, AGR2, etc.) and adjacent stroma (collagens type I, III, and V, etc.), thus reinforcing the concept of a continuous crosstalk between the two compartments in both primary tumours and their metastases. The expression of S100P, SFN, VCAN and collagens was further validated in additional primary PDACs and matched liver metastatic lesions, while the functional significance of one of the most highly expressed genes, S100P, was studied in more detail. We show that this protein increases the transendothelial migration of PDAC cancer cells in vitro, which was also confirmed in vivo experiments using a zebrafish embryo model. Thus S100P facilitates cancer cell intravasation/extravasation, critical steps in the hematogenous dissemination of pancreatic cancer cells.

Related: Cancer of the Pancreas Pancreatic Cancer


Kanojia D, Zhou W, Zhang J, et al.
Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice.
Proteomics. 2012; 12(22):3407-15 [PubMed] Related Publications
Human epidermal growth factor receptor 2 (HER2) overexpression leads to mammary tumorigenesis and its elevated levels lead to increase in cancer stem cells (CSCs), invasion, and metastasis. CSCs are resistant to radiation/chemotherapeutic drugs and are believed to be responsible for recurrence/relapse of cancer. CSCs are isolated using flow cytometry based sorting, although reliable, this technology hinders the convenient identification of molecular targets of CSCs. Therefore to understand the molecular players of increased CSC through HER2 overexpression and to develop meaningful targets for combination therapy, we isolated and characterized breast CSCs through convenient tumorsphere culture. We identified the altered protein expression in CSC as compared to non-CSC using LC-MS/MS and confirmed those results using qRT-PCR and Western blotting. Ferritin heavy chain 1 (FTH1) was identified as a candidate gene, which is involved in iron metabolism and iron depletion significantly decreased the self-renewal of CSCs. We further performed in silico analysis of altered genes in tumorsphere and identified a set of genes (PTMA, S100A4, S100A6, TNXRD1, COX-1, COX-2, KRT14, and FTH1), representing possible molecular targets, which in combination showed a promise to be used as prognostic markers for breast cancer.


Barrio MM, Abes R, Colombo M, et al.
Human macrophages and dendritic cells can equally present MART-1 antigen to CD8(+) T cells after phagocytosis of gamma-irradiated melanoma cells.
PLoS One. 2012; 7(7):e40311 [PubMed] Free Access to Full Article Related Publications
Dendritic cells (DC) can achieve cross-presentation of naturally-occurring tumor-associated antigens after phagocytosis and processing of dying tumor cells. They have been used in different clinical settings to vaccinate cancer patients. We have previously used gamma-irradiated MART-1 expressing melanoma cells as a source of antigens to vaccinate melanoma patients by injecting irradiated cells with BCG and GM-CSF or to load immature DC and use them as a vaccine. Other clinical trials have used IFN-gamma activated macrophage killer cells (MAK) to treat cancer patients. However, the clinical use of MAK has been based on their direct tumoricidal activity rather than on their ability to act as antigen-presenting cells to stimulate an adaptive antitumor response. Thus, in the present work, we compared the fate of MART-1 after phagocytosis of gamma-irradiated cells by clinical grade DC or MAK as well as the ability of these cells to cross present MART-1 to CD8(+) T cells. Using a high affinity antibody against MART-1, 2A9, which specifically stains melanoma tumors, melanoma cell lines and normal melanocytes, the expression level of MART-1 in melanoma cell lines could be related to their ability to stimulate IFN-gamma production by a MART-1 specific HLA-A*0201-restricted CD8(+) T cell clone. Confocal microscopy with Alexa Fluor®(647)-labelled 2A9 also showed that MART-1 could be detected in tumor cells attached and/or fused to phagocytes and even inside these cells as early as 1 h and up to 24 h or 48 h after initiation of co-cultures between gamma-irradiated melanoma cells and MAK or DC, respectively. Interestingly, MART-1 was cross-presented to MART-1 specific T cells by both MAK and DC co-cultured with melanoma gamma-irradiated cells for different time-points. Thus, naturally occurring MART-1 melanoma antigen can be taken-up from dying melanoma cells into DC or MAK and both cell types can induce specific CD8(+) T cell cross-presentation thereafter.

Related: MLANA Melanoma


Stenzig J, Schweikert A, Piasecki A, et al.
Progesterone receptor variants associated with the PROGINS haplotype exhibit functional properties similar to those of wild-type progesterone receptor.
Pharmacogenet Genomics. 2012; 22(8):629-41 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: The progesterone receptor (PR) is a ligand-activated transcription factor existing in two isoforms, A (PRA) and B (PRB), resulting from alternative promoter usage. It has long been speculated that genetic variants of PR are associated with the risk for various benign and malignant diseases, but data from clinical trials and in-vitro studies remain contradictory. The most extensively studied variant is termed PROGINS and consists of an intronic 320-bp Alu insertion and two coding (Ser344Thr, Val660Leu) and one silent single nucleotide polymorphism in complete linkage disequilibrium (allele frequency in Caucasians 9-19%). Our study aimed at elucidating the functional consequences of the PROGINS-associated single nucleotide polymorphisms of PRA and PRB (i.e. Thr344 and Leu660) as compared with wild-type PR (Ser344, Val660).
METHODS: The two PRA and two PRB full-length receptor variants were expressed by adenovirus in the PR-negative human breast cancer cell line T47D-Y and assayed with respect to transactivational properties, c-src activation, combined net mRNA and protein stability and hormone-binding characteristics.
RESULTS: In all experiments the wild-type PR and the PROGINS variant were undistinguishable.
CONCLUSION: Though there still might be tissue specific effects of the variants, our data indicate that these common PR variants do not functionally differ, which may provide a basis to explain the heterogeneous outcome of association studies.

Related: Breast Cancer Polymorphisms


Kilańczyk E, Graczyk A, Ostrowska H, et al.
S100A6 is transcriptionally regulated by β-catenin and interacts with a novel target, lamin A/C, in colorectal cancer cells.
Cell Calcium. 2012; 51(6):470-7 [PubMed] Related Publications
In this paper we document an increased expression of S100A6, a calcium binding protein of the S100 family, and its co-localization with β-catenin in colorectal cancer tissues and in metastatic, SW620, versus non-metastatic, SW480, human colorectal cancer cell lines. Moreover, we show up-regulation of the S100A6 protein level in non-metastatic SW480 cells due to overexpression of β-catenin as well as the activation of the S100A6 gene promoter upon cell transfection with β-catenin and the TCF-Lef1 transcription factor. Since we found a high level of S100A6 in metastatic SW620 cells we searched for its interacting partners in the protein extract prepared from these cells. Using several methods we found that S100A6 interacts with lamin A/C, a protein known to be implicated in colon carcinogenesis. Our results reveal a novel and important network of relations and interactions between proteins potentially involved in colorectal cancer development and progression.

Related: Colorectal (Bowel) Cancer CTNNB1 gene


Ouelaa-Benslama R, De Wever O, Hendrix A, et al.
Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchymal transition.
Int J Oncol. 2012; 41(1):189-200 [PubMed] Related Publications
The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype associated with chemotherapy resistance in epithelial cancers. However, the mechanisms underlying the EMT and its associated signaling dysfunctions are still poorly understood. In two genetic models of MCF-7 breast cancer cells induced to EMT by WISP-2 silencing and Snail transformation, we investigated the status of several signaling elements downstream of G-protein receptors (GPR) and their functional roles in the invasive growth potential. We report that the E-cadherin repressors Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a triple negative phenotype (loss of estrogen ERα and progesterone PRA/PRB receptors, no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor and induction of the invasive growth in collagen type I gels. Ectopic Snail expression suppressed WISP-2 transcripts and down-regulated WISP-2 gene promoter expression in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were depleted in these two convergent models of BC cell EMT. The EMT caused dominance of several proinvasive pathways downstream of GPR, including GαGβγ subunits, PKCα, AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell cycle), in line with inhibition of the p27kip1/cyclin-dependent kinase CDK3 cascade. RNA interference or selective inhibitors targeting GαGβγ subunits (BIM-46187, gallein), PKCα (Gö6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin) alleviated the invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated protein kinases. Our study suggests that the signaling protagonists GαGβγ, PKCα and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic targets in the management of clinical BC in EMT.

Related: Breast Cancer AKT1 Signal Transduction


Liu S, Guo Y, Huang R, et al.
Gene and doxorubicin co-delivery system for targeting therapy of glioma.
Biomaterials. 2012; 33(19):4907-16 [PubMed] Related Publications
The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in U87 MG cells, and accumulated in tumor more efficiently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efficacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.

Related: Apoptosis Doxorubicin


Lora V, Grings AO, Capp E, et al.
Gene and protein expression of progesterone receptor isoforms A and B, p53 and p21 in myometrium and uterine leiomyoma.
Arch Gynecol Obstet. 2012; 286(1):119-24 [PubMed] Related Publications
PURPOSE: To assess gene and protein expression of progesterone receptor isoforms A and B, cell cycle regulators p53 and p21 in leiomyoma and myometrium.
METHODS: Samples were collected from 14 patients in reproductive age who underwent abdominal hysterectomy. Gene expression of PRA, PRB, p53 and p21 was analyzed by real-time PCR. Protein expression was assessed by Western blots.
RESULTS: There was no change in gene and protein expression of PRA and PRB in both tissues. The ratio between isoforms (PRA:PRB) was not different between tissues and showed a strong correlation (r = 0.767, P = 0.004). The analysis of gene expression and protein showed increased levels of mRNA and protein p53 in leiomyoma compared to myometrium (P = 0.030 and P = 0.002, respectively). The same increase was observed in p21 mRNA levels (P = 0.016) and protein p21 levels (P = 0.026) in samples of uterine leiomyoma.
CONCLUSIONS: PRA:PRB ratio is similar in normal myometrium and leiomyomas. p53 and p21 mRNA and protein levels are increased in leiomyomas.

Related: CDKN1A TP53


van der Horst PH, Wang Y, Vandenput I, et al.
Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
PLoS One. 2012; 7(1):e30840 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).
METHODOLOGY AND PRINCIPAL FINDINGS: Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.
CONCLUSION: Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.

Related: Endometrial (Uterus) Cancer Endometrial Cancer FOXP3


Ning X, Sun S, Zhang K, et al.
S100A6 protein negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation and tumorigenesis.
PLoS One. 2012; 7(1):e30185 [PubMed] Free Access to Full Article Related Publications
Calcyclin-binding protein (CacyBP/SIP), identified on the basis of its ability to interact with S100 proteins in a calcium-dependent manner, was previously found to inhibit the proliferation and tumorigenesis of gastric cancer cells in our laboratory. Importantly, the effects of S100 proteins on the biological behavior of CacyBP/SIP in gastric cancer remain unclear. Herein, we report the construction of eukaryotic expression vectors for wild-type CacyBP/SIP and a truncated mutant lacking the S100 protein binding domain (CacyBP/SIPΔS100). The expressions of the wild-type and truncated recombinant proteins were demonstrated by transfection of MKN45 gastric cancer cells. Co-immunoprecipitation assays demonstrated interaction between S100A6 and wild-type CacyBP/SIP in MKN45 cells. Removal of the S100 protein binding domain dramatically reduced the affinity of CacyBP/SIP for S100 proteins as indicated by reduced co-immunoprecipitation of S100A6 by CacyBP/SIPΔS100. The MTT assay, FACS assay, clonogenic assay and tumor xenograft experiment were performed to assess the effect of CacyBP/SIP on cell growth and tumorigenesis in vitro and in vivo. Overexpression of CacyBP/SIP inhibited the proliferation and tumorigenesis of MKN45 gastric cancer cells; the proliferation and tumorigenesis rates were even further reduced by the expression of CacyBP/SIPΔS100. We also showed that S100 proteins negatively regulate CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation, through an effect on β-catenin protein expression and transcriptional activation of Tcf/LEF. Although the underlying mechanism of action requires further investigation, this study provides new insight into the interaction between S100 proteins and CacyBP/SIP, which might enrich our knowledge of S100 proteins and be helpful for our understanding of the development of gastric cancer.

Related: Stomach Cancer Gastric Cancer CTNNB1 gene


Tamai H, Miyake K, Yamaguchi H, et al.
AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice.
Blood. 2012; 119(1):64-71 [PubMed] Related Publications
Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-α and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-α, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL.

Related: Apoptosis Acute Lymphocytic Leukemia (ALL) HOXA9 gene IL24 (MDA7)


Li J, Riau AK, Setiawan M, et al.
S100A expression in normal corneal-limbal epithelial cells and ocular surface squamous cell carcinoma tissue.
Mol Vis. 2011; 17:2263-71 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To study the expression and cellular distribution of multiple S100A genes and proteins in normal corneal-limbal epithelium and ocular surface squamous cell carcinoma (SCC) tissue.
METHODS: Normal corneal-limbal tissue was obtained from the Lions Eye Bank, Tampa, FL. Ocular surface SCC tissues were excised from patients undergoing surgery at Singapore National Eye Centre. S100A mRNA expression was measured by quantitative PCR. S100 protein distribution was determined by immunofluorescent staining analysis.
RESULTS: Twelve S100 mRNAs were identified in human corneal and limbal epithelial cells. S100A2, A6, A8, A9, A10, and A11 mRNA was expressed at high level, while S100A1, A3, A4, A5, A6, A7, and A12 mRNA expression was low. The intracellular localization of S100A2, A6, A8, A9, A10 and A11 protein was determined in normal corneal-limbal and SCC tissues. S100A2 and S100A10 proteins were enriched in basal limbal epithelial cells of the normal tissue. S100A8 and S100A9 were found only at the surface of peripheral corneal and limbal epithelium. S100A6 was uniformly found at the plasma membrane of corneal and limbal epithelial cells. S100A11 was found at the supralayer limbal epithelial cells adjacent to the conjunctiva. SCC tissue showed typical pathological changes with expression of cytokeartin (CK) 14 and CK4 in the epithelial cells. All SCC epithelial cells were positive of S100A2, S100A10, S100A6 and S100A11 staining. Intracellular staining of S100A8 and S100A9 was found in several layers of SCC epithelium. Expression of S100A2 and S100A10 decreased dramatically in cultured limbal epithelial cells with increased passaging, which was accompanied by a small increase of S100A9 mRNA, with no changes of S100A8 gene expression. Serum and growth hormone depletion of the culture serum caused a small reduction of S100A2 and S100A10 gene expression, which was accompanied by a small increase of S100A9 mRNA while no changes of S100A8 expression was measured.
CONCLUSIONS: Normal corneal and limbal epithelial cells express a broad spectrum of S100 genes and proteins. Ocular surface SCC express high levels of S100A2, S100A10, S100A8 and S100A9 proteins. The expression of S100A2 and S100A10 is associated with limbal epithelial cell proliferation and differentiation.


Khan JA, Amazit L, Bellance C, et al.
p38 and p42/44 MAPKs differentially regulate progesterone receptor A and B isoform stabilization.
Mol Endocrinol. 2011; 25(10):1710-24 [PubMed] Free Access to Full Article Related Publications
Progesterone receptor (PR) isoforms (PRA and PRB) are implicated in the progression of breast cancers frequently associated with imbalanced PRA/PRB expression ratio. Antiprogestins represent potential antitumorigenic agents for such hormone-dependent cancers. To investigate the mechanism(s) controlling PR isoforms degradation/stability in the context of agonist and antagonist ligands, we used endometrial and mammary cancer cells stably expressing PRA and/or PRB. We found that the antiprogestin RU486 inhibited the agonist-induced turnover of PR isoforms through active mechanism(s) involving distinct MAPK-dependent phosphorylations. p42/44 MAPK activity inhibited proteasome-mediated degradation of RU486-bound PRB but not PRA in both cell lines. Ligand-induced PRB turnover required neosynthesis of a mandatory down-regulating partner whose interaction/function is negatively controlled by p42/44 MAPK. Such regulation strongly influenced expression of various endogenous PRB target genes in a selective manner, supporting functional relevance of the mechanism. Interestingly, in contrast to PRB, PRA stability was specifically increased by MAPK kinase kinase 1-induced p38 MAPK activation. Selective inhibition of p42/p44 or p38 activity resulted in opposite variations of the PRA/PRB expression ratio. Moreover, MAPK-dependent PR isoforms stability was independent of PR serine-294 phosphorylation previously proposed as a major sensor of PR down-regulation. In sum, we demonstrate that MAPK-mediated cell signaling differentially controls PRA/PRB expression ratio at posttranslational level through ligand-sensitive processes. Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis.

Related: Breast Cancer Endometrial (Uterus) Cancer Endometrial Cancer


Orr B, Riddick AC, Stewart GD, et al.
Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate.
Oncogene. 2012; 31(9):1130-42 [PubMed] Free Access to Full Article Related Publications
The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers.

Related: Prostate Cancer


Neubauer NL, Ward EC, Patel P, et al.
Progesterone receptor-B induction of BIRC3 protects endometrial cancer cells from AP1-59-mediated apoptosis.
Horm Cancer. 2011; 2(3):170-81 [PubMed] Free Access to Full Article Related Publications
Progesterone is a growth inhibitory hormone in the endometrium. While progestins can be used for the treatment of well-differentiated endometrial cancers, resistance to progestin therapy occurs for reasons that remain unclear. We have previously demonstrated that progesterone receptors (PR) A and B differentially regulate apoptosis in response to overexpression of the forkhead transcription factor, FOXO1. In this study, we further examined the PR-isoform-dependent cellular response to the AKT pathway. Treatment of PRA and PRB-expressing Ishikawa cells (PRA14, PRB23), with an AKT inhibitor API-59CJ-OMe (API-59) promoted apoptosis in the presence and absence of the ligand, R5020 preferentially in PRA14 cells. Upon PR knockdown using small interfering RNA, an increase in apoptosis was observed in PRB23 cells treated with API-59 with or without R5020 while there was no influence in PRA14 cells. Using an apoptosis-focused real-time PCR array, genes regulated by API-59 and R5020 were identified both common and unique to PRA14 and PRB23 cells. BIRC3 was identified as the only gene regulated by R5020 which occurred only in PRB cells. Knockdown of BIRC3 in PRB23 cells promoted a decrease in cell viability in response to API-59 + R5020. Furthermore, the important role of inhibitors of apoptosis (IAPs) in the PRB23 cells to promote cell survival was demonstrated using an antagonist to IAPs, a second mitochondria-derived activator of caspase (Smac also known as DIABLO) mimetic. Treatment of PRB23 cells with Smac mimetic increased apoptosis in response to API-59 + R5020. In summary, our findings indicate a mechanism by which PRB can promote cell survival in the setting of high AKT activity in endometrial cancer cells.

Related: Apoptosis Endometrial (Uterus) Cancer Endometrial Cancer AKT1 BIRC3 gene


Tonack S, Patel S, Jalali M, et al.
Tetracycline-inducible protein expression in pancreatic cancer cells: effects of CapG overexpression.
World J Gastroenterol. 2011; 17(15):1947-60 [PubMed] Free Access to Full Article Related Publications
AIM: To establish stable tetracycline-inducible pancreatic cancer cell lines.
METHODS: Suit-2, MiaPaca-2, and Panc-1 cells were transfected with a second generation reverse tetracycline-controlled transactivator protein (rtTA2S-M2), under the control of either a cytomegalovirus (CMV) or a chicken β-actin promoter, and the resulting clones were characterised.
RESULTS: Use of the chicken (β-actin) promoter proved superior for both the production and maintenance of doxycycline-inducible cell lines. The system proved versatile, enabling transient inducible expression of a variety of genes, including GST-P, CYP2E1, S100A6, and the actin capping protein, CapG. To determine the physiological utility of this system in pancreatic cancer cells, stable inducible CapG expressors were established. Overexpressed CapG was localised to the cytoplasm and the nuclear membrane, but was not observed in the nucleus. High CapG levels were associated with enhanced motility, but not with changes to the cell cycle, or cellular proliferation. In CapG-overexpressing cells, the levels and phosphorylation status of other actin-moduating proteins (Cofilin and Ezrin/Radixin) were not altered. However, preliminary analyses suggest that the levels of other cellular proteins, such as ornithine aminotransferase and enolase, are altered upon CapG induction.
CONCLUSION: We have generated pancreatic-cancer derived cell lines in which gene expression is fully controllable.

Related: Cancer of the Pancreas Pancreatic Cancer


Pathiraja TN, Shetty PB, Jelinek J, et al.
Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients.
Clin Cancer Res. 2011; 17(12):4177-86 [PubMed] Free Access to Full Article Related Publications
PURPOSE: ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
EXPERIMENTAL DESIGN: We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
RESULTS: Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
CONCLUSIONS: Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.

Related: Breast Cancer


Shehu A, Albarracin C, Devi YS, et al.
The stimulation of HSD17B7 expression by estradiol provides a powerful feed-forward mechanism for estradiol biosynthesis in breast cancer cells.
Mol Endocrinol. 2011; 25(5):754-66 [PubMed] Free Access to Full Article Related Publications
Our laboratory has previously cloned and purified an ovarian protein found to be a novel 17β-hydroxysteroid dehydrogenase type 7 enzyme (HSD17B7) (formerly prolactin receptor-associated protein) that converts the weak estrogen, estrone, to the highly potent estradiol. The regulation of this enzyme has not yet been explored. In this report, we show high expression of HSD17B7 in human ductal carcinoma and breast cancer cell lines and present evidence for a strong up-regulation of this enzyme by estradiol at the level of mRNA, protein expression, and promoter activity in MCF-7 cells. The effect of estradiol is mediated by estrogen receptor (ER)α, whereas ERβ prevents this stimulation. ER antagonists, ICI 182,780 and 4-hydroxytamoxifen, prevent estradiol-induced stimulation of the endogenously expressed HSD17B7, suggesting that these inhibitors not only block estradiol action but also its production. We have identified a -185-bp region of the hsd17b7 promoter that is highly conserved among rat, mouse, and human and confers regulation by estradiol in MCF-7 cells. This region is devoid of a classical estradiol-response element but contains a nuclear factor 1 (NF1) site that is essential for estradiol action. We found that estradiol stimulates the recruitment and DNA binding of NF1 to this region of the hsd17b7 promoter. Furthermore, knockdown of NF1 family members, NF1B, NF1A, and NF1X, completely prevents induction of this gene by estradiol. In summary, our findings demonstrate that estradiol stimulates HSD17B7 transcriptional activity in breast cancer cells through a novel mechanism requiring NF1 and strongly suggest a positive feedback mechanism to increase local estradiol synthesis causing growth of estrogen-dependent breast cancers.

Related: Breast Cancer ESR1


Hua Z, Chen J, Sun B, et al.
Specific expression of osteopontin and S100A6 in hepatocellular carcinoma.
Surgery. 2011; 149(6):783-91 [PubMed] Related Publications
BACKGROUND: Our aim was to identify differential expression of genes in hepatocellular carcinoma (HCC) with the ultimate goal of discovering novel diagnostic and therapeutic targets.
METHODS: We examined differences in gene expression between HCC and noncancerous liver tissue using a cDNA array with probes for 15,843 genes/clones. Two genes, osteopontin (OPN) and S100A6, were found to be >10-fold differentially expressed, and were selected for further immunohistochemical staining in 51 HCC and 10 nonmalignant liver specimens. The relation between OPN and S100A6 alterations and various clinicopathologic parameters was also evaluated.
RESULTS: We found a total of 219 genes that were differentially expressed >3-fold. Of these, 109 were upregulated and 110 downregulated. Within this group, 123 genes, including 59 upregulated and 64 downregulated, had been identified previously. These known genes were mainly involved in cell migration, cytoskeleton dynamics, the signaling pathway and cell cycle, and metabolism. OPN expression and S100A6 expression were seen in 26 of 51 (51.0 %) and 16 of 51 (31.4 %) HCC samples, respectively. More importantly, proteins coded by these genes were not found in any noncancerous liver specimen by immunohistochemical analysis. Expression of these genes correlated with poor differentiation (OPN: P = .013; S100A6: P = .008).
CONCLUSION: OPN, a secreted phosphoprotein that has been increasingly implicated in the progression and metastasis of cancer, and S100A6, a member of the S100 protein family that can perform cell proliferation, differentiation, migration, and cytoskeletal dynamics, may be promising diagnostic markers and therapeutic targets for HCC. In addition, the results encourage future studies involving the roles of these proteins in the development and progression of this cancer.

Related: Liver Cancer


Jung EM, Choi KC, Jeung EB
Expression of calbindin-D28k is inversely correlated with proapototic gene expression in hydrogen peroxide-induced cell death in endometrial cancer cells.
Int J Oncol. 2011; 38(4):1059-66 [PubMed] Related Publications
Calbindin-D28k (CaBP-28k) is a calcium binding protein important for intracellular Ca2+ buffering and known to have anti-apoptotic properties in neurons, osteoblasts and male germ cells. Although endometrial cancer is a common invasive gynecologic malignancy, the involvement of uterine CaBP-28k in apoptotic signaling of endometrial cancer is poorly understood. The present study investigates the role of CaBP-28k in hydrogen peroxide (H2O2)-induced apoptotic signaling in human endometrial Ishikawa cells. The dose- and time-dependent effect of H2O2 on Bax, p53 and Bcl-2 expression was assessed by Western blot analysis. Treatment of cells with 1 mM H2O2 for 1 h induced an increase in Bax and p53 expression, but the expression of Bcl-2 was not affected by H2O2 treatment. Interestingly, overexpression of CaBP-28k inhibited cell death and caused a decrease in Bax, p53 and caspase 3 expression during H2O2-induced apoptosis, suggesting that CaBP-28k blocks the up-regulation of apoptosis-related gene expression. siRNA knockdown of CaBP-28k resulted in an elevation of H2O2-induced cell death and an increase in Bax, p53 and caspase 3, providing additional evidence that induction of the CaBP-28k gene might be associated with survival signaling during H2O2-mediated cell death. Overall, these results suggest that CaBP-28k expression is inversely correlated with pro-apoptotic gene expression in human endometrial Ishikawa cells.

Related: Apoptosis CASP3 Endometrial (Uterus) Cancer Endometrial Cancer TP53


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Cite this page: Cotterill SJ. S100A6, Cancer Genetics Web: http://www.cancerindex.org/geneweb/S100A6.htm Accessed: date

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