Fulvestrant (ICI 182 780, ICI) has been used in treating patients with
hormone-sensitive
breast cancer, yet initial or acquired resistance to endocrine
therapies frequently arises and, in particular,
cancer recurs as
metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to
matrigel in MCF-7
breast cancer cells, with increased
autolysis of
calpain 1 (large subunit) and proteolysis of
focal adhesion kinase (FAK), indicating
calpain activation. Additionally, either E2 or ICI induced down-regulation of
estrogen receptor α without affecting
G protein coupled
estrogen receptor 30 (GPR30) expression. Interestingly,
GPR30 agonist G1 triggered
calpain 1
autolysis but not
calpain 2, whereas ER agonist
diethylstilbestrol caused no apparent
calpain autolysis. Furthermore, the actions of E2 and ICI on
calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated
protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by
U0126 profoundly impeded
calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by
calpain-specific inhibitors, ALLN or
calpeptin, suggesting requirement of
calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-
calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce
metastasis and improve the efficacy of
antiestrogens in treatment of advanced
breast cancer.