Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

Abstract

BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide

“…In the current study we set out to examine how a selective ERb with strong pharmacodynamic properties (16,46) could be combined with existing therapies to enhance potency further, and what might be the genomic impact. Supportively, ERb is expressed at comparable levels across prostate cell models, and it regulates proliferation and invasiveness including in ADT-recurrent models such as 22Rv1 cells.…”

Analysis of Breast Cancer Differences between China and Western Countries Based on Radiogenomics

“…To reduce the image quality difference between cases in multiple institutions, we selected MRI images obtained by the same scanner, and a total of 91 patients were obtained; Downloaded the gene expression RNAseq data from the GDC TCGA Breast Cancer dataset from UCSC Xena [ 32 ] ( accessed on 1 November 2021). These transcriptome data correspond to patients with imaging data; Downloaded GSE116180 [ 33 ], GSE197894 [ 34 ], and GSE198545 [ 35 ] from the GEO database as validation datasets. …”

“…Downloaded GSE116180 [ 33 ], GSE197894 [ 34 ], and GSE198545 [ 35 ] from the GEO database as validation datasets.…”

Modulating the Activity of Androgen Receptor for Treating Breast Cancer

“…The AR can also up-regulate tumor suppressor genes, such as the tumor suppressors SEC14L2 , EAF2 and ZBTB16 , to repress tumor growth directly [ 19 ]. Furthermore, the AR can up-regulate the expression of the tumor suppressor protein, estrogen receptors beta (ERβ), to indirectly inhibit the biological activity of ERα and down-regulate the expression level of the proto-oncogene CCND1 , or may enhance other tumor suppressors, including FOXO1 and FOXO3a [ 20 , 21 ]. Due to these activities against ERα, patients with an ERα+ve/AR+ve phenotype would have relatively better clinical features, e.g., smaller tumor [ 22 , 23 ], and longer survival time indicated by disease-free survival (DFS), overall survival (OS) and recurrence-free survival (RFS) [ 24 , 25 , 26 ].…”