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A novel oncogenic enhancer of estrogen receptor-positive breast cancer.

ABSTRACT: Estrogen receptor-positive (ER⁺) breast cancer accounts for the majority of breast cancers diagnosed, and nearly 20% of patients do not respond to endocrine therapy. The pathogenesis of ER⁺ breast cancer has not been well elucidated. The enhancer is a cis-regulatory element that promotes gene transcription and plays an important role in the spatiotemporal expression of cellular genes. Nevertheless, the oncogenic enhancer and its role in the occurrence and progression of cancer remain unclear. Here, we report a novel oncogenic enhancer (named αE _myc ) for c-Myc and reveal its activation mechanism in ER⁺ breast cancer. The results demonstrated that αE _myc enhanced the transcription of downstream genes more than 20-fold. The deletion of the 7-bp region (GGTTGCA) in αE _myc significantly downregulated the expression of c-Myc, resulting in cell nuclear changes, cell-cycle arrest, cell apoptosis, and finally, remarkable inhibition of cell proliferation. In conclusion, the present study discovers a novel oncogenic enhancer αE _myc (801 base pairs [bp], at Chr8: 127668529-127669329) and offers a remarkable core enhancer target (GGTTGCA) of αE _myc for gene therapy of ER⁺ breast cancer.

SUBMITTER: Bao C

PROVIDER: S-EPMC9463563 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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A novel oncogenic enhancer of estrogen receptor-positive breast cancer.

Bao Chunjie C Duan Jialun J Xie Ying Y Liu Yixuan Y Li Peishan P Li Jianwei J Zhao Huihui H Guo Haitao H Men Yanchen Y Ren Yuxin Y Xu Jiarui J Wang Guiling G Lu Wanliang W

Molecular therapy. Nucleic acids 20220824

Estrogen receptor-positive (ER+) breast cancer accounts for the majority of breast cancers diagnosed, and nearly 20% of patients do not respond to endocrine therapy. The pathogenesis of ER+ breast cancer has not been well elucidated. The enhancer is a cis-regulatory element that promotes gene transcription and plays an important role in the spatiotemporal expression of cellular genes. Nevertheless, the oncogenic enhancer and its role in the occurrence and progression ...[more]

PMID: 36159594

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Project description: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.

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A novel oncogenic enhancer of estrogen receptor-positive breast cancer.

Publications

A novel oncogenic enhancer of estrogen receptor-positive breast cancer.

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