Effects of Endocrine Interventions Targeting ERα or PR on Breast Cancer Risk in the General Population and Carriers of BRCA1/2 Pathogenic Variants.

There is evidence suggesting that endocrine interventions such as hormone replacement therapy and hormonal contraception can increase breast cancer (BC) risk. Sexual steroid hormones like estrogens have long been known for their adverse effects on BC development and progression via binding to estrogen receptor (ER) α. Thus, in recent years, endocrine interventions that include estrogens have been discussed more and more critically, and their impact on different BC subgroups has increasingly gained interest. Carriers of pathogenic variants in BRCA1/2 genes are known to have a high risk of developing BC and ovarian cancer. However, there remain open questions to what extent endocrine interventions targeting ERα or the progesterone receptor further increase cancer risk in this subgroup. This review article aims to provide an overview and update on the effects of endocrine interventions on breast cancer risk in the general population in comparison to BRCA1/2 mutation carriers. Finally, future directions of research are addressed, to further improve the understanding of the effects of endocrine interventions on high-risk pathogenic variant carriers.

Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma.

BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-ß type 1 receptors (TGF-ß1Rs). BAMBI lacks a kinase domain and functions as a TGF-ß1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-ß1R signaling. TGF-ß is the best-studied ligand of TGF-ßRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.

Icb-1 expression inhibits growth and fulvestrant response of breast cancer cells and affects survival of breast cancer patients.

PURPOSE: Human gene icb-1 recently has been reported to be part of a gene expression score predicting response to antiestrogen fulvestrant in breast cancer patients. In the present study, we examined to what extent icb-1 expression would affect the response of breast cancer cells to this antiestrogen in vitro and investigated underlying molecular mechanisms. Using open access mRNA data, we elucidated the significance of icb-1 expression for survival of breast cancer patients. METHODS: Icb-1 gene expression was knocked down by RNAi. Breast cancer cell growth after treatment with fulvestrant was assessed using the Cell Titer Blue assay. Gene expression was analyzed by Western blot analysis or RT-qPCR. Survival analyses were performed using bioinformatical online tools and data. RESULTS: Knockdown of icb-1 in T-47D breast cancer cells significantly increased growth of this cell line and also elevated the growth-stimulatory effect of E2 (p < 0.001). After treatment with different concentrations of fulvestrant, icb-1 knockdown cells exhibited a significantly enhanced response to this drug (p < 0.01). On the molecular level, icb-1 knockdown led to elevated expression of ESR1 and its target gene TFF1 (pS2) and enhanced E2-triggered up-regulation of proliferation genes. Finally, bioinformatical meta-analysis of gene expression data of 3951 breast cancer patients revealed that high icb-1 expression increases their relapse-free survival (HR = 0.87, p < 0.05). CONCLUSION: The presented data further support a tumor-suppressive role of icb-1 in breast cancer and suggest an inhibitory effect of this gene on fulvestrant action, which both are suggested to be mediated by suppression of cellular E2 response.

GPER-1 expression is associated with a decreased response rate to primary tamoxifen therapy of breast cancer patients.

PURPOSE: Endocrine therapies using tamoxifen and/or aromatase inhibitors are important therapeutic options for the targeted treatment of hormone-responsive breast cancer. In addition to nuclear estrogen receptors ERα and ß, G-protein-coupled estrogen receptor GPER-1 is a third receptor-mediating estrogen effects in breast cancer cells. The aim of this study was to examine to what extent GPER-1 expression might affect the efficacy of primary endocrine treatment of breast cancer. METHODS: GPER-1 expression was determined in tissue samples from patients with early breast cancer by means of immunohistochemistry and a GPER-1 score of ≥ 3 was considered to be positive. In a total of 165 patients, the response to a primary therapy with tamoxifen (TAM) or aromatase inhibitors (AI) was assessed by ultrasound imaging for up to 6 months. The primary endpoint of this study was the response to treatment evaluated by RECIST 1.1 criteria. RESULTS: GPER-1 expression was observed in 127 (77.0%) out of 165 cases. Based on GPER-1 expression and the type of endocrine treatment, the patients were divided into 4 groups: GPER-1 negative/TAM (12.1%), GPER-1 negative/AI (10.9%), GPER-1 positive/TAM (44.8%), and GPER-1 positive/AI (32.1%). The groups were well balanced regarding different clinical and pathological factors. After 4 and 6 months of treatment, a high level of stable disease or progressive disease was observed in the GPER-1 positive/TAM group only (p < 0.0001), whereas in the other three groups of patients, the most common objective response was classified as partial response. We observed a continuous reduction of mean tumor size in patients treated with aromatase inhibitors irrespective of the GPER-1 status and in GPER-1 negative patients treated with TAM. In contrast, in GPER-1 positive patients treated with TAM, a reduction of mean tumor size was observed only in the first 2 months after beginning of treatment. Four and six months after start of treatment, no reduction, but even a slight increase of tumor size was observed in this patients group. CONCLUSIONS: GPER-1 expression is significantly associated with a reduced effect of primary treatment with tamoxifen in breast cancer patients.

Knockdown of estrogen receptor ß increases proliferation and affects the transcriptome of endometrial adenocarcinoma cells.

BACKGROUND: Estrogen receptor ß (ERß) has been repeatedly suggested to play important roles in hormone-dependent cancer like in tumors of the breast, ovary or prostate. In this study, we intended to further elucidate its role in endometrial cancer. METHODS: For this purpose, we knocked down ERß expression in two endometrial cancer cell lines, the ERα-negative/ERß-positive line HEC-1A and the ERα/ß-positive cell line RL95/2, by means of siRNA transfection. Cell proliferation after transfection was assessed using the fluorescent CTB Assay (Promega). In order to elucidate possible molecular mechanisms which might underlie the effect on proliferation, we performed transcriptome analyses by means of human Affymetrix Human Gene Chip 2.0. Additionally, we treated the employed cell lines with different ERß modulators to examine their effect on proliferation. RESULTS: siRNA-mediated knockdown of ERß significantly increased proliferation of both endometrial cancer cell lines. In HEC-1A cells, proliferation was significantly increased 4, 5 and 6 days after transfection, with a maximum of about 1.7-fold (p < 0.05) on day 6. Endometrial RL95/2 cells with an ERß knockdown exhibited a clearly enhanced proliferation on day 3 and days 4 to 8, when even 2.4-fold higher numbers of viable cells were detected (p < 0.01). Transcriptome analysis revealed that this was accompanied by increased expression of several genes being known to be upregulated in cancer, including proliferation-associated genes and oncogenes, and by repression of genes associated with differentiation, apoptosis or growth inhibition. Corroborating the observed knockdown effects, treatment with the ERß antagonists PHTTP and (R, R) THC was also able to induce proliferation of both cell lines. CONCLUSIONS: Our data clearly support the putative role of ERß as tumor suppressor in endometrium as previously suggested in studies on other tissues and encourage further studies to find out to what extent this molecule might be a potential therapy target in this cancer entity.

Chemerin and Cancer.

Chemerin is a multifunctional adipokine with established roles in inflammation, adipogenesis and glucose homeostasis. Increasing evidence suggest an important function of chemerin in cancer. Chemerin's main cellular receptors, chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and C-C chemokine receptor-like 2 (CCRL2) are expressed in most normal and tumor tissues. Chemerin's role in cancer is considered controversial, since it is able to exert both anti-tumoral and tumor-promoting effects, which are mediated by different mechanisms like recruiting innate immune defenses or activation of endothelial angiogenesis. For this review article, original research articles on the role of chemerin and its receptors in cancer were considered, which are listed in the PubMed database. Additionally, we included meta-analyses of publicly accessible DNA microarray data to elucidate the association of expression of chemerin and its receptors in tumor tissues with patients' survival.

Estrogen receptor ß is associated with expression of cancer associated genes and survival in ovarian cancer.

BACKGROUND: In ovarian cancer, the role of estrogen receptors (ERs), particularly of ERß, being suggested as tumor suppressor in breast and prostate cancer, remains unclear. We examined the expression of nuclear and cytoplasmic ERß in ovarian cancer and correlated it with expression of ovarian cancer markers CA125, CEA and CA72-4, steroid hormone receptors ERα and PR, cancer-associated genes EGFR, p53, HER2 and proliferation marker Ki-67. Additionally we examined to what extent expression of ERß and the other proteins affects survival of ovarian cancer patients. METHODS: We established a tissue microarray from 171 ovarian cancer patients and performed immunohistochemical analyses of the mentioned proteins. RESULTS: Nuclear ERß was detected in 47.31% of the ovarian cancer tissues and cytoplasmic expression of this receptor was observed in 23.08%. Nuclear expression of ERß was significantly decreased in the G3 subgroup compared to better differentiated cancers (p <  0.01) and correlated with ovarian cancer markers CEA (95% CI 0.1598-0.4465; p <  0.0001) and CA72-4 (95% CI 0.05953-0.3616; p <  0.01). Cytoplasmic ERß expression correlated with EGFR levels (95% CI 0.1059-0.4049; p <  0.001). ERα expression was associated with expression of CA125 and PR. Overall survival of patients with tumors expressing cytoplasmic ERß was significant longer compared to those with ERß-negative ovarian cancer (chi-square statistic of the log-rank, p < 0.05). Progression-free survival was dependent on expression of PR (chi-square statistic of the log-rank, p < 0.05) and Ki-67 (p = 0.05). CONCLUSIONS: Our data suggest an important, but distinct role of nuclear and cytoplasmic ERß expression in ovarian cancer and encourage further studies on its role in this cancer entity.

Effect of estrogen receptor ß agonists on proliferation and gene expression of ovarian cancer cells.

BACKGROUND: Estrogen receptor (ER) ß has been suggested to affect ovarian carcinogenesis. We examined the effects of four ERß agonists on proliferation and gene expression of two ovarian cancer cell lines. METHODS: OVCAR-3 and OAW-42 ovarian cancer cells were treated with the ERß agonists ERB-041, WAY200070, Liquiritigenin and 3ß-Adiol and cell growth was measured by means of the Cell Titer Blue Assay (Promega). ERß expression was knocked down by transfection with specific siRNA. Additionally, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. To confirm the results of DNA microarray analysis, Western blot experiments were performed. RESULTS: All ERß agonists tested significantly decreased proliferation of OVCAR-3 and OAW-42 cells at a concentration of 10 nM. Maximum antiproliferative effects were induced by flavonoid Liquiritigenin, which inhibited growth of OVCAR-3 cells by 31.2% after 5 days of treatment, and ERB-041 suppressing proliferation of the same cell line by 29.1%. In OAW-42 cells, maximum effects were observed after treatment with the ERß agonist WAY200070, inhibiting cell growth by 26.8%, whereas ERB-041 decreased proliferation by 24.4%. In turn, knockdown of ERß with specific siRNA increased cell growth of OAW-42 cells about 1.9-fold. Transcriptome analyses revealed a set of genes regulated by ERß agonists including ND6, LCN1 and PTCH2, providing possible molecular mechanisms underlying the observed antiproliferative effects. CONCLUSION: In conclusion, the observed growth-inhibitory effects of all ERß agonists on ovarian cancer cell lines in vitro encourage further studies to test their possible use in the clinical setting.

Human Chorionic Gonadotropin and Breast Cancer.

Breast cancer is well known as a malignancy being strongly influenced by female steroids. Pregnancy is a protective factor against breast cancer. Human chorionic gonadotropin (HCG) is a candidate hormone which could mediate this antitumoral effect of pregnancy. For this review article, all original research articles on the role of HCG in breast cancer were considered, which are listed in PubMed database and were written in English. The role of HCG in breast cancer seems to be a paradox. Placental heterodimeric HCG acts as a protective agent by imprinting a permanent genomic signature of the mammary gland determining a refractory condition to malignant transformation which is characterized by cellular differentiation, apoptosis and growth inhibition. On the other hand, ectopic expression of ß-HCG in various cancer entities is associated with poor prognosis due to its tumor-promoting function. Placental HCG and ectopically expressed ß-HCG exert opposite effects on breast tumorigenesis. Therefore, mimicking pregnancy by treatment with HCG is suggested as a strategy for breast cancer prevention, whereas targeting ß-HCG expressing tumor cells seems to be an option for breast cancer therapy.

Agonists and knockdown of estrogen receptor ß differentially affect invasion of triple-negative breast cancer cells in vitro.

BACKGROUND: Estrogen receptor ß (ERß) is expressed in the majority of invasive breast cancer cases, irrespective of their subtype, including triple-negative breast cancer (TNBC). Thus, ERß might be a potential target for therapy of this challenging cancer type. In this in vitro study, we examined the role of ERß in invasion of two triple-negative breast cancer cell lines. METHODS: MDA-MB-231 and HS578T breast cancer cells were treated with the specific ERß agonists ERB-041, WAY200070, Liquiritigenin and 3ß-Adiol. Knockdown of ERß expression was performed by means of siRNA transfection. Effects on cellular invasion were assessed in vitro by means of a modified Boyden chamber assay. Transcriptome analyses were performed using Affymetrix Human Gene 1.0 ST microarrays. Pathway and gene network analyses were performed by means of Genomatix and Ingenuity Pathway Analysis software. RESULTS: Invasiveness of MBA-MB-231 and HS578T breast cancer cells decreased after treatment with ERß agonists ERB-041 and WAY200070. Agonists Liquiritigenin and 3ß-Adiol only reduced invasion of MDA-MB-231 cells. Knockdown of ERß expression increased invasiveness of MDA-MB-231 cells about 3-fold. Transcriptome and pathway analyses revealed that ERß knockdown led to activation of TGFß signalling and induced expression of a network of genes with functions in extracellular matrix, tumor cell invasion and vitamin D3 metabolism. CONCLUSIONS: Our data suggest that ERß suppresses invasiveness of triple-negative breast cancer cells in vitro. Whether ERß agonists might be useful drugs in the treatment of triple-negative breast cancer, has to be evaluated in further animal and clinical studies.

Polymorphisms in the promoter region of estrogen receptor ß gene in endometrial cancer.

INTRODUCTION: The development of endometrial cancer is known to be affected by estrogens. Thus, genetic variations like single nucleotide polymorphisms (SNPs) in genes involved in estrogen biosynthesis, metabolism, and signal transduction might affect risk for endometrial cancer. In this study, we tested the hypothesis that polymorphisms in the promoter of ESR2 gene may be associated with susceptibility to this disease. METHODS: We compared the frequency of three SNPs in the promoter region of ESR2 gene (rs2987983, rs3020450, and rs3020449) in 135 women with endometrial cancer and 135 healthy women serving as controls by means of allele-specific tetra-primer PCR. RESULTS: Regarding allele frequency, allele positivity or genotype frequencies of these SNPs we did not observe any significant difference between healthy women and women with endometrial cancer. CONCLUSION: Our data clearly suggest that the tested SNPs in the promotor region of human ESR2 gene are not associated with the development of endometrial cancer.

Effects of a combined treatment with tamoxifen and estrogen receptor ß agonists on human breast cancer cell lines.

INTRODUCTION: Coexpression of estrogen receptors (ER) α and ß is present in about half of all breast cancer cases. Whereas ERα is a well-established target for endocrine therapy with the selective estrogen receptor modulator tamoxifen, the applicability of ERß as target in breast cancer therapy is unclear. In this study, we examined the effects of two synthetic ERß agonists alone and in combination with tamoxifen on ERα/ß-positive breast cancer cells. METHODS: We treated MCF-7 and T-47D breast cancer cells with the ERß agonists ERB-041 and WAY-200070 and measured the effects on cell growth. In addition, transcriptome analyses were performed by means of Affymetrix GeneChip arrays. RESULTS: When given alone, ERß agonists ERB-041 and WAY-200070 did not affect the growth of MCF-7 or T-47D cells. In contrast, addition of these drugs to tamoxifen increased its growth-inhibitory effect on both cell lines. This effect was more pronounced under serum-free conditions, but was also observed in the presence of serum in T-47D cells. Transcriptome analyses revealed a set of genes regulated after addition of ERß agonists including S100A8 and CD177. CONCLUSION: The observed enhanced growth-inhibitory effects of a combination of tamoxifen and ERß agonists in vitro encourage further studies to test its possible use in the clinical setting.

Expression of SCUBE2 gene declines in high grade endometrial cancer and associates with expression of steroid hormone receptors and tumor suppressor PTEN.

SCUBE2 (Signal peptide-CUB-epidermal growth factor-like domain-containing 2) gene codes for a cell-surface glycoprotein. In breast cancer, SCUBE2 transcript levels are part of important prognostic and predictive gene signatures and are linked to expression of estrogen receptor α (ERα). To elucidate the role of this gene in endometrial cancer, we compared SCUBE2 expression in malignant and normal endometrial tissue specimens. We then examined its correlation with steroid hormone receptors and PTEN and compared it to SCUBE2 expression in breast cancer samples. Expression of SCUBE2 was found to be decreased in G3 endometrial cancer when compared to postmenopausal endometrium or to G1 tumors (p < 0.05). In postmenopausal endometrium, SCUBE2 transcript levels were more than twice as high as in premenopausal women. In breast cancer, SCUBE2 expression was found to be notably reduced particularly in ERα-negative G3 tumors. Both in endometrial and breast cancer we observed a significant positive correlation of SCUBE2 transcript levels with expression of ERα, PR and PTEN. Our data suggest that SCUBE2, like in breast cancer, associates with ERα and might have a potential as prognostic or predictive marker in endometrial cancer.

Estrogens and Estrogen Receptor Modulators in Cancer Research and Therapy.

Estrogens affect oncogenesis and tumor progression in a variety of cancer entities [...].

Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer.

The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance.

Chemerin and Chemokine-like Receptor 1 Are Not Prognostic in Colorectal Carcinoma.

BACKGROUND/AIM: Colorectal carcinoma is a commonly diagnosed malignancy. The chemoattractant protein chemerin was shown to regulate immune response, angiogenesis, and cell migration and has a role in gastrointestinal cancers. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) are expressed in the colon and here, their diagnostic and prognostic value in colorectal carcinoma was examined. PATIENTS AND METHODS: Chemerin and CMKLR1 protein were quantified by immunohistochemistry in tumor tissues of 86 patients with colorectal cancer. Associations with tumor stage, tumor grade, lymph node score, tumor recurrence, and survival were calculated. RESULTS: Chemerin was not detectable in 12%, low expressed in 55%, medium expressed in 27%, and highly abundant in 7% of the tumors. CMKLR1 protein levels were low in 25%, medium in 70%, and high in 5% of the tumors. Chemerin protein expression was slightly induced in larger tumors of males. CMKLR1 protein expression was modestly higher in the tumors of patients with local and/or distal disease recurrence. CMKLR1 and chemerin protein in colorectal cancer tissues were not related to tumor grade or lymph node score. CD3, CD4, and CD8 protein expression did not correlate with chemerin or CMKLR1. Tumor chemerin and CMKLR1 protein levels were similar in survivors and non-survivors. CONCLUSION: In colorectal carcinoma, chemerin and CMKLR1 proteins are weakly associated with tumor stage and tumor recurrence. Levels of these proteins in colorectal carcinoma tissues are not connected with patients' survival.

Role of Estrogen Receptor ß, G-Protein Coupled Estrogen Receptor and Estrogen-Related Receptors in Endometrial and Ovarian Cancer.

Ovarian and endometrial cancers are affected by estrogens and their receptors. It has been long known that in different types of cancers, estrogens activate tumor cell proliferation via estrogen receptor α (ERα). In contrast, the role of ERs discovered later, including ERß and G-protein-coupled ER (GPER1), in cancer is less well understood, but the current state of knowledge indicates them to have a considerable impact on both cancer development and progression. Moreover, estrogen related receptors (ERRs) have been reported to affect pathobiology of many tumor types. This article provides a summary and update of the current findings on the role of ERß, GPER1, and ERRs in ovarian and endometrial cancer. For this purpose, original research articles on the role of ERß, GPER1, and ERRs in ovarian and endometrial cancers listed in the PubMed database have been reviewed.

Chemerin and Chemokine-like Receptor 1 Expression Are Associated with Hepatocellular Carcinoma Progression in European Patients.

The chemoattractant protein chemerin is protective in experimental hepatocellular carcinoma (HCC), and high expression in HCC tissues of Asian patients was related to a favorable prognosis. Studies from Asia found reduced expression of chemerin in HCC compared to para-tumor tissues while our previous analysis observed the opposite. Aim of this study was to correlate chemerin expression in HCC tissues with disease severity of European patients Hepatocyte chemerin protein expression was assessed by immunohistochemistry in HCC tissue of 383 patients, and was low in 24%, moderate in 49% and high in 27%. High chemerin protein in the HCC tissues was related to the T stage, vessel invasion, histologic grade, Union for International Cancer Control (UICC) stage and tumor size. Chemokine-like receptor 1 (CMKLR1) is a functional chemerin receptor. CMKLR1 protein in hepatocytes was low expressed in HCC tissues of 36%, moderate in tissues of 32% and high in 32% of the HCCs. Tumor CMKLR1 was associated with the T stage, vessel invasion, histologic grade and UICC stage. Notably, sex-specific analysis revealed that associations of chemerin and CMKLR1 expression with HCC progression were significant in males but not in females. The tumor chemerin and CMKLR1 protein expression were not related to steatosis, inflammation and fibrosis grades. In summary, chemerin as well as CMKLR1 protein were related to disease severity of European HCC patients, and this was significant in males. This observation is in contrast to Asian patients where higher chemerin in the tumors was protective. Current analysis provides evidence for ethnicity and sex-related differences of tumor expressed chemerin and HCC severity.

Chemerin and Chemokine-like Receptor 1 Expression in Ovarian Cancer Associates with Proteins Involved in Estrogen Signaling.

Chemerin, a pleiotropic adipokine coded by the RARRES2 gene, has been reported to affect the pathophysiology of various cancer entities. To further approach the role of this adipokine in ovarian cancer (OC), intratumoral protein levels of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were examined by immunohistochemistry analyzing tissue microarrays with tumor samples from 208 OC patients. Since chemerin has been reported to affect the female reproductive system, associations with proteins involved in steroid hormone signaling were analyzed. Additionally, correlations with ovarian cancer markers, cancer-related proteins, and survival of OC patients were examined. A positive correlation of chemerin and CMKLR1 protein levels in OC (Spearman's rho = 0.6, p < 0.0001) was observed. Chemerin staining intensity was strongly associated with the expression of progesterone receptor (PR) (Spearman´s rho = 0.79, p < 0.0001). Both chemerin and CMKLR1 proteins positively correlated with estrogen receptor ß (ERß) and estrogen-related receptors. Neither chemerin nor the CMKLR1 protein level was associated with the survival of OC patients. At the mRNA level, in silico analysis revealed low RARRES2 and high CMKLR1 expression associated with longer overall survival. The results of our correlation analyses suggested the previously reported interaction of chemerin and estrogen signaling to be present in OC tissue. Further studies are needed to elucidate to which extent this interaction might affect OC development and progression.

Network analysis of icb-1 gene function in human breast cancer cells.

Icb-1 is a human gene previously described by our group to exert important functions in cancer cells of different origin. We now performed microarray-based gene expression profiling with subsequent network modeling to further elucidate the role of icb-1 in breast cancer cells. Analyzing the effect of icb-1 knockdown on the transcriptome of MCF-7 cells, we found 151 differentially expressed genes exhibiting more than twofold changes, 97 of which were up- and 54 downregulated. Most of the upregulated genes were cancer-related genes associated with poor prognosis, invasion and metastasis, building an oncogenic network of TNF target genes. On the other hand, network analysis identified the downregulated genes to be primarily involved in interferon signaling and cellular apoptosis. Confirming these network data, we observed that cells with reduced levels of icb-1 exhibited an impaired response to the apoptosis inducers tamoxifen, staurosporine, actinomycin, and camptothecin. The data of this study suggest that icb-1 might exert a tumor-suppressor function in breast cancer and that its loss might confer relative resistance of breast cancer cells to apoptotic drugs.