期刊
MOLECULAR AND CELLULAR ENDOCRINOLOGY
卷 229, 期 1-2, 页码 161-173出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2004.08.002
关键词
estrogen; insulin; IGF-1; c-Myc; 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 pathway 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. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
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