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Transcriptional Activity of an Estrogen Receptor ? Subtype in the Medaka Oryzias dancena.

ABSTRACT: In vertebrate reproductive system, estrogen receptor (ER) plays a pivotal role in mediation of estrogenic signaling pathways. In the present study, we report the cDNA cloning, expression analysis, and transcriptional activity of ER?1 subtype from medaka Oryzias dancena. The deduced O. dancena ER?1 (odER?1; 519 amino acids) contained six characteristic A/B to E/F domains with very short activation function 2 region (called AF2). A phylogenetic analysis indicated that odER?1 was highly conserved among teleost ER?1 subgroup. A conventional RT-PCR revealed that the odER?1 transcripts were widely distributed in the multiple tissues, the ovary, brain, gill, intestine, kidney, and muscle. Further, the relatively higher odER?1 expressions in the ovary and brain were clearly reproduced in RT-qPCR assay. When HA-fused odER?1 expression vector was transfected into HEK293 cells, an immunoreactivity for odER?1 was mainly detected in the nucleus part. Finally, an estrogen responsive element driven luciferase reporter assays demonstrated that the transcriptional activity of odER?1 significantly increased by estradiol-17? (E2) in a dose dependent manner (p<0.05). However, fold-activation of odER?1 in the presence of E2 was markedly weak, when it compared with those of O. latipes ER?1. Taken together, these data suggest that odER?1 represents a functional variant of teleost ER? subtype and provides a basic tool allowing future studies examining the function of F domain of ER?1 subtype and expanding our knowledge of ER? evolution.

SUBMITTER: Maeng S

PROVIDER: S-EPMC6985291 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Transcriptional Activity of an Estrogen Receptor β Subtype in the Medaka Oryzias dancena.

Maeng Sejung S Yoon Sung Woo SW Kim Eun Jeong EJ Nam Yoon Kwon YK Sohn Young Chang YC

Development & reproduction 20191231 4

In vertebrate reproductive system, estrogen receptor (ER) plays a pivotal role in mediation of estrogenic signaling pathways. In the present study, we report the cDNA cloning, expression analysis, and transcriptional activity of ERβ1 subtype from medaka Oryzias dancena. The deduced O. dancena ERβ1 (odERβ1; 519 amino acids) contained six characteristic A/B to E/F domains with very short activation function 2 region (called AF2). A phylogenetic analysis indicated that odERβ1 was high ...[more]

PMID: 31993539

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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.

Dataset Information

Transcriptional Activity of an Estrogen Receptor ? Subtype in the Medaka Oryzias dancena.

Publications

Transcriptional Activity of an Estrogen Receptor β Subtype in the Medaka <i>Oryzias dancena</i>.

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