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

Mol Cell Endocrinol. 2005 Jan 14;229(1-2):161-73. doi: 10.1016/j.mce.2004.08.002.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects*
  • Cell Proliferation / drug effects
  • Cyclin D1 / metabolism*
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Estrogens
  • Hypoglycemic Agents
  • Insulin
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Cyclin D1
  • Insulin-Like Growth Factor I
  • Mitogen-Activated Protein Kinases