4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells.

Abstract

Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells.

• Authors: Yang Li, Yan Chen, Zhu-Xia Zhu, Xiao-Hong Liu, Li Yang, Lei Wan, Ting-Wen Lei, Xu-Dong Wang
• Journal: Toxicology (Toxicology) Vol. 309 Pg. 61-5 (Jul 05 2013) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 23624423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Cyclin E
• GPER1 protein, human
• Receptors, Estrogen
• Receptors, G-Protein-Coupled
• Tamoxifen
• afimoxifene

Topics

• Breast Neoplasms (metabolism)
• Cell Movement (drug effects, physiology)
• Cyclin E (biosynthesis, genetics, metabolism)
• Female
• Humans
• MCF-7 Cells
• Protein Processing, Post-Translational
• Receptors, Estrogen (physiology)
• Receptors, G-Protein-Coupled (physiology)
• Tamoxifen (analogs & derivatives, toxicity)
• Up-Regulation (drug effects)