Overexpression of insulin receptor substrate 1 (IRS-1) in the human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth and transformation.
The synergistic action of estrogens and insulin-like growth factors (IGFs) promotes the growth of many human breast cancer cell lines. This synergistic effect involves estrogen-dependent induction of the IGF system, i.e., estrogens augment the number of IGF-I receptors, stimulate the secretion of IGF-II, and promote the synthesis of certain IGF-binding proteins. On the other hand, the sustained activation of the IGF-I receptor (IGF-IR) by the overexpression of IGF-II has been found to contribute to the development of the estrogen-independent phenotype in breast cancer cells. In this study, we have investigated whether the amplification of the IGF-IR intracellular signaling in MCF-7 cells can abolish or reduce estrogen requirements for growth and transformation. To this end we developed several MCF-7 clones that overexpressed insulin receptor substrate 1 (IRS-1), one of the principal substrates of the IGF-IR. We report here that in MCF-7 cells overexpressing IRS-1, estrogen requirements for growth in monolayer culture as well as in soft agar were reduced. The decreased estrogen requirements depended on the level of the overexpressed IRS-1 protein, and in cells which contained several-fold more functional IRS-1 than the parental cells, we observed total loss of estrogen dependence for growth. In addition, the importance of IRS-1 in proliferation of MCF-7 cells has been confirmed through the use of antisense strategies.
Surmacz
E
E
Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Burgaud
J L
JL
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014410:Tumor Stem Cell Assay
D004967:Estrogens; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; C066542:insulin receptor-related receptor