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Estrogen Receptor Beta 1: A Potential Therapeutic Target for Triple Negative Breast Cancer

ABSTRACT: Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). These receptors are well characterized and often serve as targets in breast cancer treatment. As a result, TNBCs are difficult to treat and have a high propensity to metastasize to distant organs. For these reasons, TNBCs are responsible for over 50% of all breast cancer mortalities while only accounting for 15% - 20% of breast cancer cases. However, estrogen receptor beta 1 (ERβ1) has emerged as a potential therapeutic target in the treatment of TNBCs. Using an in vivo xenograft preclinical mouse model with human TNBC, we found that expression of ERβ1 significantly reduced both primary tumor growth and metastasis in the animals. Moreover, TNBCs with elevated levels of ERβ1 showed reduction in epithelial-to-mesenchymal transition (EMT) markers and breast cancer stem cell (BCSC) markers, and increases in the expression of genes associated with inhibition of cancer cell invasiveness and metastasis, suggesting possible mechanisms underlying the antitumor activity of ERβ1. Treatment with ERβ1 agonist ligand often enhanced the suppressive activity of ERβ1, suggesting their potential utility in improving TNBC treatment. The findings enable understanding of the mechanisms by which ERβ impedes TNBC growth, invasiveness and metastasis and consideration of ways by which treatments involving ERβ might improve TNBC patient outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210092 | GEO | 2022/10/28

REPOSITORIES: GEO

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Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous disease representing the most aggressive breast cancer (BC) subtype. Lack of Estrogen Receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu) expression makes TNBC immune to common therapies, significantly limiting the treatment options and suggesting the need to identify novel therapeutic targets. It was previously reported that Estrogen Receptor beta (ERβ) is expressed in a fraction of TNBC patients, where its presence correlates with improved patient outcome. Recently, we demonstrated an oncosuppressive ERβ effect in TNBC cell models expressing exogenous ERβ. On the other hand, it was shown that ERβ is involved in miRNA-mediated gene regulation in hormone-responsive BC cells, suggesting similar effect also in TNBC. To verify this hypothesis, we performed small non-coding RNA (sncRNA) sequencing on three engineered cell lines belonging to different TNBC molecular subtypes. ERβ-specific changes of sncRNA profile revealed that the major part of deregulated molecules are subtype specific, with only few commonly regulated ones. In order to validate the obtained results, we performed sncRNA profiling of 12 ERβ positive and 32 ERβ negative TNBC tissues, whose receptor status was assessed by immunohistochemistry in our previous research. Also here, ERβ-specific group of deregulated sncRNAs was identified. Interestingly, comparison of obtained in vitro and in vivo results revealed 2 differentially expressed miRNAs, displaying the same behavior in all three analyzed cell lines and tissues. In concordance with our previous results, IPA signaling pathway analysis performed on genes targeted by deregulated miRNAs highlighted downregulation of cholesterol biosynthesis pathway and upregulation of several signaling processes. Taken together, these findings suggest that ERβ is able to exert its oncosuppressive role in TNBC through miRNA-mediated regulation of gene expression.

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Estrogen Receptor Beta 1: A Potential Therapeutic Target for Triple Negative Breast Cancer

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