GPER mediates activation of HIF1α/VEGF signaling by estrogens.

Ernestina Marianna De Francesco,Michele Pellegrino,Rosamaria Lappano,Maria Francesca Santolla,Sergio Abonante,Emilia Ricchio,Marcello Maggiolini

doi:10.1158/0008-5472.can-13-3590

Ernestina Marianna De Francesco, Michele Pellegrino + Show 5 more

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https://doi.org/10.1158/0008-5472.can-13-3590

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Abstract

Biological responses to estrogens in normal and malignant tissues are mainly mediated by the estrogen receptors ERα and ERβ, which function as ligand-activated transcription factors. In addition, the G protein-coupled receptor GPR30 (GPER) mediates estrogenic signaling in breast cancer cells and cancer-associated fibroblasts (CAF) that contribute to cancer progression. In this study, we evaluated the role elicited by GPER in the estrogen-regulated expression and function of vascular endothelial growth factor (VEGF) in ER-negative breast cancer cells and CAF. We demonstrated that 17β-estradiol (E2) and the GPER-selective ligand G-1 triggered a GPER/EGFR/ERK/c-fos signaling pathway that leads to increased VEGF via upregulation of HIF1α. In further extending the mechanisms involved in E2-supported angiogenesis, we also showed that conditioned medium from CAF treated with E2 and G-1 promoted human endothelial tube formation in a GPER-dependent manner. In vivo, ligand-activated GPER was sufficient to enhance tumor growth and the expression of HIF1α, VEGF, and the endothelial marker CD34 in a mouse xenograft model of breast cancer. Our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HIF1α-dependent VEGF expression that supports angiogenesis and progression in breast cancer.

Highlights

Breast cancer is the most frequently diagnosed malignancy in women in the United States and the leading cause of cancerrelated death in women worldwide [1]
The aforementioned findings were confirmed by immunofluorescence experiments performed in both SkBr3 cells (Fig. 2) and cancer-associated fibroblasts (CAF) (Supplementary Fig. S2), further corroborating the involvement of GPER in the upregulation of vascular endothelial growth factor (VEGF) protein expression induced by estrogens in these cells
We have demonstrated that GPER mediates the upregulation of VEGF expression induced by E2 and G-1 in breast cancer cells and CAFs

Summary

Introduction

Breast cancer is the most frequently diagnosed malignancy in women in the United States and the leading cause of cancerrelated death in women worldwide [1]. The G protein–coupled receptor (GPR)30/GPER has been shown to mediate estrogenic signaling in different normal and malignant cell contexts, including breast cancer [3,4,5,6,7]. In this regard, the identification of selective GPER agonists or antagonists [8,9,10,11,12] has allowed the evaluation of certain biological responses elicited through GPER.

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