Abstract

The central involvement of estrogen in the development of the mammary gland and in the genesis of breast cancer has lent impetus to studies of the links between estrogen action and the cell cycle machinery. Recent studies of the estrogenic regulation of molecules with known roles in the control of G1/S phase progression have resulted in significant advances in understanding these links. Estrogens independently regulate the expression and function of c-Myc and cyclin D1 and the induction of either c-Myc or cyclin D1 is sufficient to recapitulate the effects of estrogen on cell cycle progression. These pathways converge at the activation of cyclin E-Cdk2 complexes. The active cyclin E-Cdk2 complexes are depleted of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) because of estrogen-mediated inhibition of nascent p21(WAF1/CIP1). Insulin and estrogen synergistically stimulate cell cycle progression, and the ability of estrogen to antagonize an insulin-induced increase in p21(WAF1/CIP1) gene expression appears to underlie this effect. Antiestrogen treatment of MCF-7 cells leads to an acute decrease of c-Myc expression, a subsequent decline in cyclin D1, and ultimately arrest of cells in a state with features characteristic of quiescence. An antisense-mediated decrease in c-Myc expression results in decreased cyclin D1 expression and inhibition of DNA synthesis, mimicking the effects of antiestrogen treatment and emphasizing the importance of c-Myc as an estrogen/antiestrogen target. These data identify c-Myc, cyclin D1, p21(WAF1/CIP1) and cyclin E-Cdk2 as central components of estrogen regulation of cell cycle progression and hence as potential downstream targets that contribute to the role of estrogen in oncogenesis.