title: Progestins reinitiate cell cycle progression in antiestrogen-arrested breast cancer cells through the B-isoform of progesterone receptor.
abstract: Estrogen treatment of MCF-7 human breast cancer cells allows the reinitiation of synchronous cell cycle progression in antiestrogen-arrested cells. Here, we report that progestins also reinitiate cell cycle progression in this model. Using clonal cell lines derived from progesterone receptor (PR)-negative MCF-7M13 cells expressing wild-type or mutant forms of PRA and PRB, we show that this effect is mediated via PRB, not PRA. Cell cycle progression did not occur with a DNA-binding domain mutant of PRB but was unaffected by mutation in the NH(2)-terminal, SH3 domain interaction motif, which mediates rapid progestin activation of c-Src. Thus, the progestin-induced proliferative response in antiestrogen-inhibited cells is mediated primarily by the transcriptional activity of PRB. Analysis of selected cell cycle targets showed that progestin treatment induced levels of cyclin D1 expression and retinoblastoma protein (Rb) phosphorylation similar to those induced by estradiol. In contrast, progestin treatment resulted in only a 1.2-fold induction of c-Myc compared with a 10-fold induction by estradiol. These results support the conclusion that progestin, in a PRB-dependent manner, can overcome the growth-inhibitory effects of antiestrogens in estrogen receptor/PR-positive breast cancer cells by the induction of cyclin D1 expression. The mediation of this effect by PRB, but not PRA, further suggests a mechanism whereby abnormal regulation of the normal expression ratios of PR isoforms in breast cancer could lead to the attenuation of antiestrogen-mediated growth arrest.
authors: Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors: Eileen M
authors: EM
authors: McGowan
authors: Amanda J
authors: AJ
authors: Russell
authors: Viroj
authors: V
authors: Boonyaratanakornkit
authors: Darren N
authors: DN
authors: Saunders
authors: Gillian M
authors: GM
authors: Lehrbach
authors: C Marcelo
authors: CM
authors: Sergio
authors: Elizabeth A
authors: EA
authors: Musgrove
authors: Dean P
authors: DP
authors: Edwards
authors: Robert L
authors: RL
authors: Sutherland
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011282:Pregnenediones / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D020847:Estrogen Receptor Modulators; C489427:MYC protein, human; D011282:Pregnenediones; D011372:Progestins; D016271:Proto-Oncogene Proteins c-myc; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D000077267:Fulvestrant; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D004958:Estradiol