Estrogen-mediated S-phase Entry

Estrogens are a class of steroid hormones that play a central role in reproduction. Estrogenic steroids which include: Estrone (E1), Estradiol/17-β, Estradiol (E2) and Estriol (E3) regulate cellular functions in a wide variety of tissues and influence proliferation in the female reproductive tract and mammary gland. It is this proliferative role of estrogen that is linked to women's risk for breast and uterine cancer. For example, in the uterus, estrogen triggers the proliferation of endometrial lining cells during each month of the menstrual cycle, followed by death of these cells during menstruation. These repeated cycles of estrogen-induced cell division tend to increase the risk of developing cancer in two ways: Estrogen can stimulate the division of uterine cells that already have DNA mutations and it can increase the chance of developing new, spontaneous mutations during repeated rounds of cell division.The effects of estrogens are mediated classically by estrogen receptors (ERs) that act as ligand-dependent transcription factors . Estrogens induce proliferation of ER-positive cells by stimulating G1/S transition which is associated with increased expression of cyclins, activation of CDKs and phosphorylation of the tumor suppressor Rb. Because CDKs control cell division, dysregulation of their regulatory partners, the cyclins, has been implicated in the initiation and promotion of hyperplasia and oncogenesis. Estrogen-induced proliferation of uterine and breast epithelium in vivo is associated with formation of active Cyclin D1-CDK4 complexes. The primary target of CDK action in G1-phase is Rb. When dephosphorylated in G1, Rb complexes with and blocks transcriptional activation by E2F transcription factors. But phosphorylation of Rb by Cyclin-CDK complexes leads to its dissociation from E2F, allowing E2F to activate the transcription of S-phase genes.Estrogens also regulate the expression and function of c-Myc and the induction of c-Myc is sufficient to recapitulate the effects of estrogen on cell cycle progression. This pathway converges at the activation of cyclin E-Cdk2 complexes. The active cyclin E-Cdk2 complexes are depleted of the CDK inhibitor p21 because of estrogen-mediated decrease in the association of p21 with the cyclin E-Cdk2 complex. The active complex is now able to phosporylate Rb setting in motion a cascade of events, leading eventually to the transcriptional activation of S-phase genes.