Insulin and insulin-like growth factor signaling are defective in the MDA MB-468 human breast cancer cell line.
Polypeptide growth factors including the insulin-like growth factors (IGFs), insulin, and transforming growth factor-alpha are mitogens for many breast cancer cell lines and may act as regulators of cancer cell growth. In a human breast cancer cell line MCF-7, which expresses IGF-I receptor (IGF-IR), stimulation with insulin or IGFs resulted in autophosphorylation of the IGF-IR in an increased proportion of ras bound to GTP and in the association of phosphatidylinositol 3'-kinase (PI3K) activity and of p85-PI3K with M(r) 185,000 phosphotyrosinylated proteins corresponding in size to insulin/IGF-IR substrates. These events were associated with enhanced proliferation. MDA MB-468 is a human breast cancer cell line which expresses insulin receptor and high levels of epidermal growth factor/transforming growth factor alpha receptor but low levels of IGF-IR. In this cell line, insulin stimulated autophosphorylation of IR at physiological concentrations and promoted the association of PI3K activity and of p85 with phosphotyrosine-containing proteins. Insulin did not, however, induce increased ras.GTP, and the cells exhibited minimal proliferation in response to insulin. Unlike insulin treatment, epidermal growth factor stimulation of MDA MB-468 cells is mitogenic and resulted in increased ras.GTP content, suggesting that the failure of insulin to induce these changes is not due to alterations in these signaling molecules. We conclude that there is a postreceptor defect in insulin signaling in MDA MB-468 which prevents the activation of ras and the induction of mitogenesis. Activation of PI3K by insulin is not sufficient to mediate mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Sepp-Lorenzino
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Breast and Gynecologic Service, Memorial Sloan Kettering Cancer Center,New York, New York 10021.
Rosen
N
N
Lebwohl
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DE
D001483:Base Sequence; D001943:Breast Neoplasms / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000187:drug effects*; D013002:Somatomedins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007328:Insulin; D013002:Somatomedins