BackgroundBreast cancer (BC) is highly heterogeneous with ~ 60–70% of estrogen receptor positive BC patient’s response to anti-hormone therapy. Estrogen receptors (ERs) play an important role in breast cancer progression and treatment. Estrogen related receptors (ERRs) are a group of nuclear receptors which belong to orphan nuclear receptors, which have sequence homology with ERs and share target genes. Here, we investigated the possible role and clinicopathological importance of ERRβ in breast cancer.MethodsEstrogen related receptor β (ERRβ) expression was examined using tissue microarray slides (TMA) of Breast Carcinoma patients with adjacent normal by immunohistochemistry and in breast cancer cell lines. In order to investigate whether ERRβ is a direct target of ERα, we investigated the expression of ERRβ in short hairpin ribonucleic acid knockdown of ERα breast cancer cells by western blot, qRT-PCR and RT-PCR. We further confirmed the binding of ERα by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), Re-ChIP and luciferase assays. Fluorescence-activated cell sorting analysis (FACS) was performed to elucidate the role of ERRβ in cell cycle regulation. A Kaplan-Meier Survival analysis of GEO dataset was performed to correlate the expression of ERRβ with survival in breast cancer patients.ResultsTissue microarray (TMA) analysis showed that ERRβ is significantly down-regulated in breast carcinoma tissue samples compared to adjacent normal. ER + ve breast tumors and cell lines showed a significant expression of ERRβ compared to ER-ve tumors and cell lines. Estrogen treatment significantly induced the expression of ERRβ and it was ERα dependent. Mechanistic analyses indicate that ERα directly targets ERRβ through estrogen response element and ERRβ also mediates cell cycle regulation through p18, p21cip and cyclin D1 in breast cancer cells. Our results also showed the up-regulation of ERRβ promoter activity in ectopically co-expressed ERα and ERRβ breast cancer cell lines. Fluorescence-activated cell sorting analysis (FACS) showed increased G0/G1 phase cell population in ERRβ overexpressed MCF7 cells. Furthermore, ERRβ expression was inversely correlated with overall survival in breast cancer. Collectively our results suggest cell cycle and tumor suppressor role of ERRβ in breast cancer cells which provide a potential avenue to target ERRβ signaling pathway in breast cancer.ConclusionOur results indicate that ERRβ is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. ERRβ could be therapeutic target for the treatment of breast cancer.
Estrogen-related receptor beta (ERRβ) is downregulated in breast cancer cells and its overexpression in breast cancer patients is positively correlated with an improved prognosis and prolonged relapse-free survival. Here, we unravelled a molecular mechanism for ERRβ downregulation in breast cancer. We found that ERRβ is a key substrate of the SCF complex and that NEDDylation can activate the Cullin subunits of the SCF complex to target ERRβ for degradation in breast cancer. Consistently, using in vitro and in vivo models, we demonstrated that MLN4924, a specific small molecule inhibitor of NEDDylation, can restore ERRβ expression and culminate in a reduction in cell proliferation and migration of breast cancer cells. We also showed that increased ERRβ expression promotes the upregulation of its target genes, including the tumour suppressors p21 Cip1/Waf1 and E-cadherin, involved in cell proliferation and migration arrest at the gene promoter level. Interestingly, this tumour suppressive role of ERRβ does not depend on the expression of ERα in breast cancer. Moreover, our data revealed that the ERRβ recruits the transcription co-activator p300 to its targeted gene promoters to upregulate their expression. Collectively, our work revealed that restoration of ERRβ expression using the NEDDylation inhibitor MLN4924 can be a novel and effective strategy for breast cancer treatment.
Breast invasive carcinoma (BRCA) is most malignant and leading cause of death in women. The efforts are ongoing for improvement in early detection, prevention and treatment. Therefore, identification of biomarkers/candidate genes has become very important. The current work includes comprehensive analysis of RNA-sequencing data of 1097 BRCA samples and 114 normal adjacent tissues to identify dysregulated genes in major molecular classes of BRCA in various clinical stages. Huge number of dysregulated genes were found, some were stage-specific, and others were common. The pathways as interferon signaling, tryptophan degradation III, granulocyte adhesion & diapedesis and catecholamine biosynthesis were found in ER/PR+/HER-2-(p-value<0.010), pathways as RAR activation, adipogenesis, role of JAK1, JAK2 in interferon signaling, TGF-β and STAT3 signaling (p-value<0.014) intricated in ER/PR-/HER-2+ and pathways as IL-1/IL-8 signaling, TNFR1/TNFR2 signaling, TWEAK and relaxin signaling (p-value<0.005) were found in triple negative breast cancer. The genes were clustered based on their mutation profile which revealed nine mutated clusters, some of which were known to be involved in well-known cancer signalling pathways while others were less characterized. Each cluster was analyzed in detail which led us to discover genes viz. NLGN3, MAML2, TTN, SYNE1, ANK2 as candidates in BRCA. The genes were found to be involved in important processes as chemotaxis, axon guidance, notch binding, cell-adhesion-molecule binding etc. They are central genes in the protein-protein-interaction network indicating they can have important regulatory roles. The qRT-PCR and western blot confirmed our findings in breast cancer cell-lines. Further, immunohistochemistry corroborated the results in ~100 tissue samples. The genes can be used as biomarker in BRCA.
Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+ dependent class III histone deacetylase (HDAC) which plays a vital role in cell survival, senescence and metabolism. SIRT1 is overexpressed in several cancers, including breast cancer. Due to the lack of endocrine therapy for ER-ve breast cancers, it is essential to identify the molecular targets having therapeutic importance. SIRT1 is a known target gene of estrogen receptor α (ERα) and well associated with ERα deacetylation. Transcription factor Estrogen related receptors (ERRs) share sequence homology with ERs in DNA binding domain, therefore possibility of sharing target genes between them is high. Our present study aim to elucidate the role of ERRβ in the regulation of SIRT1 in breast cancer tumorigenesis. SIRT1 was highly up-regulated in ER + ve breast cancer cells and tissues. Analysis of 5’ upstream region of SIRT1 suggested the presence of six putative ERRE sites and in-vitro and in-vivo studies confirmed the binding of ERRβ to them. We found SIRT1 to be up-regulated in ERRβ overexpressed ER + ve breast cancer cells. Furthermore, our results suggested the up-regulation of SIRT1 upon ectopic expression of ERRβ along with PCAF. We also proved the tumorigenic role of SIRT1 with enough evidence showing the significant role of SIRT1 in cell proliferation, migration and colony formation capacity. Collectively our results suggest the tumorigenic role of SIRT1 in the breast cancer and SIRT1 inhibitors might serve as potential therapeutic drugs for the treatment of breast cancer.
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