G protein-coupled estrogen receptor is apoptotic and correlates with increased distant disease-free survival of estrogen receptor-positive breast cancer patients.

Abstract

PURPOSE:

G protein-coupled estrogen receptor 1 (GPER1), previously named GPR30, is a membrane receptor reported to mediate nongenomic estrogen responses. We investigated if GPER1 expression correlates with any clinicopathologic variables and distant disease-free survival (DDFS) in patients with breast cancer, if any prognostic impact of the receptor is dependent on estrogen receptor-α (ER-α) status, and if the receptor impacts apoptotic signaling in ER-positive breast cancer cells.

EXPERIMENTAL DESIGN:

GPER1 expression was analyzed by immunohistochemistry in breast tumors from 273 pre- and postmenopausal stage II patients, all treated with adjuvant tamoxifen for 2 years (cohort I) and from 208 premenopausal lymph node-negative patients, of which 87% were not subjected to any adjuvant systemic treatment (cohort II). GPER1-dependent proapoptotic signaling was analyzed in MCF7 cells with and without GPER1 knockdown, T47D cells, HEK293 cells (HEK), and HEK stably expressing GPER1 (HEK-R).

RESULTS:

GPER1 positively correlates with ER and progesterone receptor expression. Multivariate analysis showed that GPER1 is an independent prognostic marker of increased 10-year DDFS in the ER-positive subgroup. HEK-R has higher basal proapoptotic signaling compared with HEK including increased cytochrome C release, caspase-3 cleavage, PARP cleavage, and decreased cell viability. Treating HEK-R with the proteasome inhibitor epoxomicin, to decrease GPER1 degradation, further increases receptor-dependent proapoptotic signaling. Also, GPER1 knockdown decreases basal and agonist-stimulated proapoptotic receptor signaling in MCF7 cells.

CONCLUSIONS:

GPER1 is a prognostic indicator for increased DDFS in ER-positive breast cancer, which may be associated with constitutive GPER1-dependent proapoptotic signaling in ER-positive breast cancer cells.

• Authors: Stefan Broselid, Benxu Cheng, Martin Sjöström, Kristina Lövgren, Heather L P Klug-De Santiago, Mattias Belting, Karin Jirström, Per Malmström, Björn Olde, Pär-Ola Bendahl, Linda Hartman, Mårten Fernö, L M Fredrik Leeb-Lundberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 7 Pg. 1681-92 (Apr 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23554355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• GPER1 protein, human
• Receptors, Estrogen
• Receptors, G-Protein-Coupled

Topics

• Adult
• Aged
• Aged, 80 and over
• Apoptosis (genetics)
• Breast Neoplasms (genetics, metabolism, mortality, pathology)
• Cell Line, Tumor
• Female
• HEK293 Cells
• Humans
• Middle Aged
• Neoplasm Staging
• Receptors, Estrogen (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)