title: The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo.
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.
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510120, China.
authors.forename: K-S
authors.initials: KS
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Tropical Disease Control (Ministry of Education), Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510655, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: H-B
authors.initials: HB
authors.lastname: Huang
authors.affiliation: Key Laboratory of Tropical Disease Control (Ministry of Education), Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510655, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China.
authors.forename: S-H
authors.initials: SH
authors.lastname: Cai
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.affiliation: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: H-S
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled