The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Academic Article uri icon

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  • 1184

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  • 1194

abstract

  • The G protein-coupled receptor GPR30 binds 17beta-estradiol (E(2)) yet differs from classic estrogen receptors (ERalpha and ERbeta). GPR30 can mediate E(2)-induced nongenomic signaling, but its role in ERalpha-positive breast cancer remains unclear. Gene expression microarray data from five cohorts comprising 1,250 breast carcinomas showed an association between increased GPR30 expression and ERalpha-positive status. We therefore examined GPR30 in estrogenic activities in ER-positive MCF-7 breast cancer cells using G-1 and diethylstilbestrol (DES), ligands that selectively activate GPR30 and ER, respectively, and small interfering RNAs. In expression studies, E(2) and DES, but not G-1, transiently downregulated both ER and GPR30, indicating that this was ER mediated. In Ca(2+) mobilization studies, GPR30, but not ERalpha, mediated E(2)-induced Ca(2+) responses because E(2), 4-hydroxytamoxifen (activates GPR30), and G-1, but not DES, elicited cytosolic Ca(2+) increases not only in MCF-7 cells but also in ER-negative SKBr3 cells. Additionally, in MCF-7 cells, GPR30 depletion blocked E(2)-induced and G-1-induced Ca(2+) mobilization, but ERalpha depletion did not. Interestingly, GPR30-coupled Ca(2+) responses were sustained and inositol triphosphate receptor mediated in ER-positive MCF-7 cells but transitory and ryanodine receptor mediated in ER-negative SKBr3 cells. Proliferation studies involving GPR30 depletion indicated that the role of GPR30 was to promote SKBr3 cell growth but reduce MCF-7 cell growth. Supporting this, G-1 profoundly inhibited MCF-7 cell growth, potentially via p53 and p21 induction. Further, flow cytometry showed that G-1 blocked MCF-7 cell cycle progression at the G(1) phase. Thus, GPR30 antagonizes growth of ERalpha-positive breast cancer and may represent a new target to combat this disease.

date/time value

  • 2010

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-09-3068

PubMed Identifier

  • 20086172

volume

  • 70

number

  • 3

keywords

  • Breast Neoplasms
  • Calcium
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclopentanes
  • Diethylstilbestrol
  • Estradiol
  • Estrogen Receptor alpha
  • Estrogens
  • Female
  • Flow Cytometry
  • G1 Phase
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Quinolines
  • RNA Interference
  • Receptors, G-Protein-Coupled
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Suppressor Protein p53