Oncotarget

Research Papers: Pathology:

GPER is involved in the stimulatory effects of aldosterone in breast cancer cells and breast tumor-derived endothelial cells

Damiano Cosimo Rigiracciolo, Andrea Scarpelli, Rosamaria Lappano, Assunta Pisano, Maria Francesca Santolla, Silvia Avino, Paola De Marco, Benedetta Bussolati, Marcello Maggiolini _ and Ernestina Marianna De Francesco

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Oncotarget. 2016; 7:94-111. https://doi.org/10.18632/oncotarget.6475

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Abstract

Damiano Cosimo Rigiracciolo1, Andrea Scarpelli1, Rosamaria Lappano1, Assunta Pisano1, Maria Francesca Santolla1, Silvia Avino1, Paola De Marco1, Benedetta Bussolati2, Marcello Maggiolini1 and Ernestina Marianna De Francesco1

1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy

2 Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy

Correspondence to:

Marcello Maggiolini, email:

Rosamaria Lappano, email:

Keywords: GPER, aldosterone, mineralcorticoid receptor, breast cancer cells, breast tumor-derived endothelial cells, Pathology Section

Received: September 01, 2015 Accepted: November 22, 2015 Published: December 05, 2015

Abstract

Aldosterone induces relevant effects binding to the mineralcorticoid receptor (MR), which acts as a ligand-gated transcription factor. Alternate mechanisms can mediate the action of aldosterone such as the activation of epidermal growth factor receptor (EGFR), MAPK/ERK, transcription factors and ion channels. The G-protein estrogen receptor (GPER) has been involved in the stimulatory effects of estrogenic signalling in breast cancer. GPER has been also shown to contribute to certain responses to aldosterone, however the role played by GPER and the molecular mechanisms implicated remain to be fully understood. Here, we evaluated the involvement of GPER in the stimulatory action exerted by aldosterone in breast cancer cells and breast tumor derived endothelial cells (B-TEC). Competition assays, gene expression and silencing studies, immunoblotting and immunofluorescence experiments, cell proliferation and migration were performed in order to provide novel insights into the role of GPER in the aldosterone-activated signalling. Our results demonstrate that aldosterone triggers the EGFR/ERK transduction pathway in a MR- and GPER-dependent manner. Aldosterone does not bind to GPER, it however induces the direct interaction between MR and GPER as well as between GPER and EGFR. Next, we ascertain that the up-regulation of the Na+/H+ exchanger-1 (NHE-1) induced by aldosterone involves MR and GPER. Biologically, both MR and GPER contribute to the proliferation and migration of breast and endothelial cancer cells mediated by NHE-1 upon aldosterone exposure. Our data further extend the current knowledge on the molecular mechanisms through which GPER may contribute to the stimulatory action elicited by aldosterone in breast cancer.


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