Abstract
There is an urgent clinical need for safe and effective treatment agents and therapy targets for estrogen receptor negative (ER−) breast cancer. G protein-coupled receptor 30 (GPR30), which mediates non-genomic signaling of estrogen to regulate cell growth, is highly expressed in ER− breast cancer cells. We here showed that activation of GPR30 by the receptor-specific agonist G-1 inhibited the growth of ER− breast cancer cells in vitro. Treatment of ER− breast cancer cells with G-1 resulted in G2/M-phase arrest, downregulation of G2-checkpoint regulator cyclin B, and induction of mitochondrial-related apoptosis. The G-1 treatment increased expression of p53 and its phosphorylation levels at Serine 15, promoted its nuclear translocation, and inhibited its ubiquitylation, which mediated the growth arrest effects on cell proliferation. Further, the G-1 induced sustained activation and nuclear translocation of ERK1/2, which was mediated by GPR30/epidermal growth factor receptor (EGFR) signals, also mediated its inhibition effects of G-1. With extensive use of siRNA-knockdown experiments and inhibitors, we found that upregulation of p21 by the cross-talk of GPR30/EGFR and p53 was also involved in G-1-induced cell growth arrest. In vivo experiments showed that G-1 treatment significantly suppressed the growth of SkBr3 xenograft tumors and increased the survival rate, associated with proliferation suppression and upregulation of p53, p21 while downregulation of cyclin B. The discovery of multiple signal pathways mediated the suppression effects of G-1 makes it a promising candidate drug and lays the foundation for future development of GPR30-based therapies for ER− breast cancer treatment.
Highlights
Breast cancer is generally classified into estrogen receptor α positive (ER+) or ER-negative (ER − ) subtypes.[2]
We found that activation of G protein-coupled receptor 30 (GPR30) by G-1 for 48 h significantly inhibited the proliferation of both SkBr3 and MDA-MB-231 cells via a concentration-dependent manner (Figure 1a )
In MDAMB-231 tumor xenografts in nude mice, initial single G-1 exposure can significantly delay in vivo growth and increase the survival rate of ER − breast cancer cells via proliferation suppression and apoptosis induction in tumor tissues
Summary
Breast cancer is generally classified into estrogen receptor α positive (ER+) or ER-negative (ER − ) subtypes.[2]. Studies revealed that activation of GPR30 can induce the expression of genes and activate pathways that facilitate cell proliferation of endometrial,[11,12] breast,[13] and ovarian cancer.[14] On the contrary, numerous studies demonstrated that activation of GPR30 by its specific agonist G-1 results in cell-cycle arrest and proliferation inhibition of ERαpositive breast cancer,[10] endothelial cells,[15] prostate,[16] and ovarian[9] cancer cells. We demonstrated that activation of GPR30 by G-1 inhibits the proliferation of ER − breast cancer cells both in vitro and in vivo
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