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Estrogen receptor-? regulation of microRNA-590 targets FAM171A1-a modifier of breast cancer invasiveness.

ABSTRACT: The pathobiology and aggressiveness of the triple negative breast cancer (TNBC) are influenced by genes that are preferentially expressed in TNBC cells. However, the nature of such genes with the role in invasiveness of TNBC cells is not fully understood. Here, we identified FAM171A1, member (A1) of the family with sequence similarity 171, as an overexpressed candidate gene in TNBC cells and tumors as compared to estrogen receptor-alpha (ER?) positive breast cancer. We found that the expression of FAM171A1 correlates well with the loss of ER? as well as its newly identified target miR590-5p in TNBC but not in ER?-positive cells. In addition, we report that ER? regulates FAM171A1 expression through a mechanism which involves ER? stimulation of miR590-5p expression via binding to its promoter, and in-turn, miR590-5p suppression of FAM171A1 expression. Further, we found that the levels of FAM171A1 correlate well with cancer cell aggressiveness as depletion or overexpression of FAM171A1 confers reduced or increased ability of TNBC cells to form mammospheres, respectively in accordance with the previous report of increased mammosphere formation potential of metastatic cells. In brief, results presented here have demonstrated that ER? regulation of FAM171A1 expression via miR590-5p explains the molecular basis of the noticed reduced levels of FAM171A1 in ER-positive breast cancer cells and that FAM171A1 is a preferably TNBC- overexpressed gene. Further, the noted loss of ER?-miR590-5p axis may upregulate the expression of FAM171A1 and consequently, resulting aggressiveness of TNBC cells. These findings suggest that FAM171A1 might represent a potentially novel therapeutic target for TNBC tumors.

SUBMITTER: Sanawar R

PROVIDER: S-EPMC6328622 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Estrogen receptor-α regulation of microRNA-590 targets FAM171A1-a modifier of breast cancer invasiveness.

Sanawar Rahul R Mohan Dan Vipin V Santhoshkumar Thankayyan R TR Kumar Rakesh R Pillai M Radhakrishna MR

Oncogenesis 20190109 1

The pathobiology and aggressiveness of the triple negative breast cancer (TNBC) are influenced by genes that are preferentially expressed in TNBC cells. However, the nature of such genes with the role in invasiveness of TNBC cells is not fully understood. Here, we identified FAM171A1, member (A1) of the family with sequence similarity 171, as an overexpressed candidate gene in TNBC cells and tumors as compared to estrogen receptor-alpha (ERα) positive breast cancer. We found that the expression ...[more]

PMID: 30631046

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Project description:BackgroundIn the year 2020, breast cancer was the most common form of cancer worldwide. Roughly 70% of breast cancers are estrogen receptor-positive (ER+). MicroRNA-190b (miR-190b) has previously been reported to be upregulated in ER+ breast cancers. Previously, we have demonstrated that miR-190b is hypomethylated in ER+ breast cancers, potentially leading to its upregulation.ObjectivesTo further study the role of miR-190b in ER+ breast cancer and to identify its clinically relevant targets in breast cancer.DesignPatient cohort and cell line-based RNA-sequencing analysis.MethodsThe Cancer Genome Atlas was used to obtain gene expression data and clinical information on patients with breast cancer. To identify messenger RNA (mRNA) targets for miR-190b, the ER+ breast cancer cell line T-47D was used to immunoprecipitate biotin-labeled miR-190b followed by RNA sequencing. Western blot was used to confirm miR-190b target. Patient survival based on miR-190b and selected target was studied using the Cancer Genome Atlas.ResultsIn this study, we confirm that miR-190b is overexpressed in breast cancer via differential expression analysis and show that high expression of miR-190b results in more favorable outcomes in Luminal A patients, hazard ratio (HR) = 0.29, 95% confidence interval [CI] = 0.12-0.71, P = .0063. MicroRNA-190b target analysis identified RING finger and WD repeat domain 3 (RFWD3) as one of miR-190b regulatory targets in ER+ breast cancer. Survival analysis of RFWD3 showed that elevated levels result in poorer overall survival in patients with Luminal A breast cancer (HR = 2.22, 95% CI = 1.33-3.71, P = .002). Gene ontology analysis of our sequencing results indicates that miR-190b may have a role in breast cancer development and/or tumorigenesis and that it may be a suitable tool in characterization between the ER+ subtypes, Luminal A, and Luminal B.ConclusionsWe show that miR-190b targets RFWD3 in ER+ breast cancers leading to lower RFWD3 protein expression. Low levels of RFWD3 are associated with better outcomes in patients with Luminal A breast cancer but not in patients with Luminal B breast cancer. These findings provide novel insights into miR-190b role in breast cancer and that its clinical relevance is subtype specific.

Project description:BACKGROUND:Breast 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 ERR? in breast cancer. METHODS:Estrogen related receptor ? (ERR?) 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 ERR? is a direct target of ER?, we investigated the expression of ERR? in short hairpin ribonucleic acid knockdown of ER? breast cancer cells by western blot, qRT-PCR and RT-PCR. We further confirmed the binding of ER? 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 ERR? in cell cycle regulation. A Kaplan-Meier Survival analysis of GEO dataset was performed to correlate the expression of ERR? with survival in breast cancer patients. RESULTS:Tissue microarray (TMA) analysis showed that ERR? 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 ERR? compared to ER-ve tumors and cell lines. Estrogen treatment significantly induced the expression of ERR? and it was ER? dependent. Mechanistic analyses indicate that ER? directly targets ERR? through estrogen response element and ERR? also mediates cell cycle regulation through p18, p21cip and cyclin D1 in breast cancer cells. Our results also showed the up-regulation of ERR? promoter activity in ectopically co-expressed ER? and ERR? breast cancer cell lines. Fluorescence-activated cell sorting analysis (FACS) showed increased G0/G1 phase cell population in ERR? overexpressed MCF7 cells. Furthermore, ERR? expression was inversely correlated with overall survival in breast cancer. Collectively our results suggest cell cycle and tumor suppressor role of ERR? in breast cancer cells which provide a potential avenue to target ERR? signaling pathway in breast cancer. CONCLUSION:Our results indicate that ERR? is a negative regulator of cell cycle and a possible tumor suppressor in breast cancer. ERR? could be therapeutic target for the treatment of breast cancer.

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Estrogen receptor-? regulation of microRNA-590 targets FAM171A1-a modifier of breast cancer invasiveness.

Publications

Estrogen receptor-α regulation of microRNA-590 targets FAM171A1-a modifier of breast cancer invasiveness.

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