title: G protein-coupled estrogen receptor is apoptotic and correlates with increased distant disease-free survival of estrogen receptor-positive breast cancer patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Broselid
authors.forename: Benxu
authors.initials: B
authors.lastname: Cheng
authors.forename: Martin
authors.initials: M
authors.lastname: Sjöström
authors.forename: Kristina
authors.initials: K
authors.lastname: Lövgren
authors.forename: Heather L P
authors.initials: HL
authors.lastname: Klug-De Santiago
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.forename: Björn
authors.initials: B
authors.lastname: Olde
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.forename: Linda
authors.initials: L
authors.lastname: Hartman
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.forename: L M Fredrik
authors.initials: LM
authors.lastname: Leeb-Lundberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled