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Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

ABSTRACT: Upregulation of estrogen receptor beta (ER?) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ER? and breast carcinogenesis is still missing.To study the role of ER? in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ER? and p53 in the mammary gland epithelium. For epithelium-specific knockout of ER? and p53, ER? F/F and p53 F/F mice were crossed to transgenic mice that express the Cre recombinase under the control of the human keratin 14 promoter.Somatic loss of ER? significantly accelerated formation of p53-deficient mammary tumors. Loss of the receptor also resulted in the development of less differentiated carcinomas with stronger spindle cell morphology and decreased expression of luminal epithelial markers.Our results show that synergism between ER? and p53 inactivation functions to determine important aspects of breast oncogenesis and cancer progression.

SUBMITTER: Bado I

PROVIDER: S-EPMC5494907 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

Bado Igor I Nikolos Fotis F Rajapaksa Gayani G Wu Wanfu W Castaneda Jessica J Krishnamurthy Savitri S Webb Paul P Gustafsson Jan-Åke JÅ Thomas Christoforos C

Breast cancer research : BCR 20170703 1

<h4>Background</h4>Upregulation of estrogen receptor beta (ERβ) in breast cancer cells is associated with epithelial maintenance, decreased proliferation and invasion, and a reduction in the expression of the receptor has been observed in invasive breast tumors. However, proof of an association between loss of ERβ and breast carcinogenesis is still missing.<h4>Methods</h4>To study the role of ERβ in breast oncogenesis, we generated mouse conditional mutants with specific inactivation of ERβ and ...[more]

PMID: 28673316

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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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Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

Publications

Somatic loss of estrogen receptor beta and p53 synergize to induce breast tumorigenesis.

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