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Open AccessArticle

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

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Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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NEURO-DOL Basics & Clinical Pharmacology of Pain, INSERM, CHU, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France
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ANALGESIA Institute, Université Clermont Auvergne, F-63000 Clermont-Ferrand, France
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CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, 87036 Rende, Italy
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Laboratoire des Biomolécules (LBM), CNRS-UMR 7203, Sorbonne University, Ecole Normale Supérieure, 75252 Paris Cedex 05, France
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Cibles Thérapeutiques et Conception de Médicaments (CiTCoM), CNRS–UMR 8038, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, 75270 Paris Cedex 06, France
*
Authors to whom correspondence should be addressed.
Future Affiliation: Cibles Thérapeutiques et Conception de Médicaments (CiTCoM), CNRS–UMR 8038, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, 75270 Paris Cedex 06, France.
Cells 2019, 8(6), 590; https://doi.org/10.3390/cells8060590
Received: 4 June 2019 / Accepted: 13 June 2019 / Published: 14 June 2019
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Breast Cancer)
The inhibition of the G protein-coupled estrogen receptor (GPER) offers promising perspectives for the treatment of breast tumors. A peptide corresponding to part of the hinge region/AF2 domain of the human estrogen receptor α (ERα17p, residues 295–311) exerts anti-proliferative effects in various breast cancer cells including those used as triple negative breast cancer (TNBC) models. As preliminary investigations have evoked a role for the GPER in the mechanism of action of this peptide, we focused our studies on this protein using SkBr3 breast cancer cells, which are ideal for GPER evaluation. ERα17p inhibits cell growth by targeting membrane signaling. Identified as a GPER inverse agonist, it co-localizes with GPER and induces the proteasome-dependent downregulation of GPER. It also decreases the level of pEGFR (phosphorylation of epidermal growth factor receptor), pERK1/2 (phosphorylation of extracellular signal-regulated kinase), and c-fos. ERα17p is rapidly distributed in mice after intra-peritoneal injection and is found primarily in the mammary glands. The N-terminal PLMI motif, which presents analogies with the GPER antagonist PBX1, reproduces the effect of the whole ERα17p. Thus, this motif seems to direct the action of the entire peptide, as highlighted by docking and molecular dynamics studies. Consequently, the tetrapeptide PLMI, which can be claimed as the first peptidic GPER disruptor, could open new avenues for specific GPER modulators. View Full-Text
Keywords: peptide; anti-proliferation; inverse agonist; desensitizer; GPER; SkBr3; breast cancer peptide; anti-proliferation; inverse agonist; desensitizer; GPER; SkBr3; breast cancer
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MDPI and ACS Style

Lappano, R.; Mallet, C.; Rizzuti, B.; Grande, F.; Galli, G.R.; Byrne, C.; Broutin, I.; Boudieu, L.; Eschalier, A.; Jacquot, Y.; Maggiolini, M. The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells. Cells 2019, 8, 590.

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