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English

A genetic polymorphism repurposes the G-protein coupled and membrane-associated estrogen receptor GPER to a transcription factor-like molecule promoting paracrine signaling between stroma and breast carcinoma cells

Contributors

Pupo, Marco; Bodmer, Alexandre; Berto, Mélissa; Maggiolini, Marcello; Dietrich, Pierre-Yves; Picard, Didier

Published in

Oncotarget, vol. 8, no. 29, p. 46728-46744

Publication date

2017

Abstract

GPER is a membrane-associated estrogen receptor of the family of G-protein coupled receptors. For breast cancer, the contribution of GPER to promoting the proliferation and migration of both carcinoma cells and cancer-associated fibroblasts (CAFs) in response to estrogen and other agonists has extensively been investigated. Intriguingly, GPER was previously found to be localized to the nucleus in one isolate of breast CAFs. Moreover, this nuclear GPER was shown to bind regulatory sequences of cancer-relevant target genes and to induce their expression. We decided to find out what induces the nuclear localization of GPER, how general this phenomenon is, and what its functional significance is. We discovered that interfering with N-linked glycosylation of GPER, either by mutation of the predicted glycosylation sites or pharmacologically with tunicamycin, drives GPER into the nucleus. Surveying a small set of CAFs from breast cancer biopsies, we found that a relatively common single nucleotide polymorphism, which results in the expression of a GPER variant with the amino acid substitution P16L, is associated with the nuclear localization of GPER. GPER with P16L fails to be glycosylated, presumably because of a conformational effect on the nearby glycosylation sites. GPER P16L is defective for membrane-associated signaling, but instead acts like an estrogen-stimulated transcription factor. In CAFs, it induces the secretion of paracrine factors that promote the migration of carcinoma cells. This raises the possibility that the GPER P16L polymorphism could be a risk factor for breast cancer.

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

PUPO, Marco et al. A genetic polymorphism repurposes the G-protein coupled and membrane-associated estrogen receptor GPER to a transcription factor-like molecule promoting paracrine signaling between stroma and breast carcinoma cells. In: Oncotarget, 2017, vol. 8, n° 29, p. 46728–46744. doi: 10.18632/oncotarget.18156

Main files (1)

Article (Published version)

Identifiers

Additional URL for this publication

http://www.oncotarget.com/fulltext/18156

Journal ISSN

1949-2553
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287downloads

Technical informations

Creation

10/08/2017 11:54:00

First validation

10/08/2017 11:54:00

Update

15/03/2023 01:55:30

Status update

15/03/2023 01:55:30

Last indexation

31/10/2024 07:33:13
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