Estrogen inhibits cell cycle progression and retinoblastoma phosphorylation in rhesus ovarian surface epithelial cell culture.
Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1 microg/ml). OSE cells express the estrogen receptor (ER)-alpha, and are the source of 90% of ovarian cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentrations of estradiol, and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol, nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells, and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.
Oregon Regional Primate Research Center, Division of Reproductive Sciences, 505 NW 185th Ave, Beaverton, OR 97006, USA. wrightj@ohsu.edu
Jay W
JW
Wright
Richard L
RL
Stouffer
Karin D
KD
Rodland
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D016193:G1 Phase; D008253:Macaca mulatta; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D013997:Time Factors
D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D004967:Estrogens; D018809:Proliferating Cell Nuclear Antigen; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D004958:Estradiol