Calycosin inhibits the in vitro and in vivo growth of breast cancer cells through WDR7-7-GPR30 Signaling

• Published in: Journal of experimental & clinical cancer research Vol. 36; no. 1; p. 153
• Main Authors: Tian, Jing, Wang, Yong, Zhang, Xing, Ren, Qianyao, Li, Rong, Huang, Yue, Lu, Huiling, Chen, Jian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02.11.2017; BioMed Central; BMC
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Calycosin; Cancer cells; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular signal transduction; Development and progression; Drug therapy; Epidermal growth factor; Estrogens; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; GPR30; Growth; Humans; Isoflavones - administration & dosage; Isoflavones - pharmacology; Kinases; Long non-coding RNA; MCF-7 Cells; Medical research; Mice; Physiological aspects; Proteins; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA, Long Noncoding - genetics; Signal Transduction - drug effects; Studies; Up-Regulation; WDR7-7; Xenograft Model Antitumor Assays; China; United States > US; GPR30; Breast cancer; Calycosin; WDR7-7; Long non-coding RNA
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-017-0625-y

Clinically, breast cancer is generally classified into estrogen receptor-positive (ER+) or estrogen receptor-negative (ER-) subtypes. The phytoestrogen calycosin has been shown to inhibit the proliferation of ER+ cells, which may be mediated by a feedback loop that involves miR-375, RAS dexamethasone-induced 1 (RASD1), and ERα. However, how calycosin acts on ER- breast cancer cells remains unclear. Here, we show that calycosin inhibited the proliferation of both ER- (MDA-MB-468 and SKBR3) and ER+ breast cancer cells (MCF-7 and T47D) and that these inhibitory effects were associated with the up-regulation of the long non-coding RNA (lncRNA) WDR7-7. For the first time, we demonstrate that the expression of WDR7-7 is reduced in breast cancer cell lines and that the overexpression of WDR7-7 inhibits growth through a mechanism that involves G-protein coupled estrogen receptor 30 (GPR30). Meanwhile, we show that calycosin stimulated the WDR7-7-GPR30 signaling pathway in MCF-7, T47D, MDA-MB-468, and SKBR3 breast cancer cells. In contrast, in MCF10A and GPR30-deficient MDA-MB-231 cells, due to a lack of WDR7-7-GPR30 for activation, calycosin failed to inhibit cell growth. Additionally, in all four GPR30-positive breast cancer lines, calycosin decreased the phosphorylation levels of SRC, EGFR, ERK1/2 and Akt, but the inhibition of WDR7-7 blocked these changes and increased proliferation. In mice bearing MCF-7 or SKBR3 xenografts, tumor growth was inhibited by calycosin, and changes in expression the levels of WDR7-7 and GPR30 in tumor tissues were similar to those in cultured MCF-7 and SKBR3 cells. These results suggest the possibility that calycosin inhibited the proliferation of breast cancer cells, at least partially, through WDR7-7-GPR30 signaling, which may explain why calycosin can exert inhibitory effects on ER- breast cancer.