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Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1


Estrogen and insulin/insulin-like growth factor-I (IGF-I) are major mitogens for breast epithelial cells and when co-administered, synergistically induce G(1)-S phase cell cycle progression. We investigated this cooperativity by evaluating if the key cell cycle regulators, c-Myc and cyclin D1, represent points of convergence in the action of these mitogens in MCF-7 breast cancer cells. These studies demonstrated that estrogen significantly increased both c-Myc and cyclin D1 protein, while insulin predominantly increased cyclin D1 levels. This cumulative increase in c-Myc and cyclin D1 contributes to the cooperativity of these mitogens, since ectopic expression of c-Myc or cyclin D1 cooperates with either the estrogen or insulin signaling pathways to increase cell cycle progression. Inhibition of the MAPK or PI3-kinase pathways significantly reduced c-Myc and cyclin D1 protein levels and cell cycle progression. Ectopic expression of cyclin D1 partially overcame this inhibition, while ectopic expression of c-Myc partially overcame MAPK but not PI3-kinase inhibition. Therefore, estrogen and insulin/IGF-1 differentially regulate c-Myc and cyclin D1 to cooperatively stimulate breast cancer cell proliferation.

Type Journal
ISBN 0303-7207 (Print)
Authors Mawson, A.;Lai, A.;Carroll, J. S.;Sergio, C. M.;Mitchell, C. J.;Sarcevic, B. :
Published Date 2005-01-01 00:00:00
Published Volume 229
Published Issue 1-2
Published Pages 161-73
Status Published In-print