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Constitutive Activation of Insulin Receptor Substrate 1 in Breast Cancer: Therapeutic Implication
Final rept. 15 Jul 2003-14 Jul 2004
BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA
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Insulin receptor substrate 1 IRS-1 was constitutively activated in the majority of breast cancers. Blocking IRS-1 signaling with a dominant-negative IRS-1 mutant F18 dramatically reduced the cancer cell growth. These studies suggest that constitutive IRS-1 activation plays a central role in breast cancer cell growth and that IRS-1 could be an attractive therapeutic target. IRS-1 has complicated downstream signaling pathways that play important roles in multiple cellular functions. An ideal IRS-1 inhibitor for cancer therapy would block only the IRS-1 growth-related signaling, with minimal interruption of other IRS-1 signaling. To determine the IRS-1 downstream signaling pathway that is critical for growth of breast cancer cells, we expressed six IRS-1 mutants, each with the mutation of critical tyrosine residues that initiates a particular IRS-i downstream pathway, in breast cancer cells and determined the dominant-negative effects of each IRS-1 mutant on tumor cell growth. Our results showed that IRS-1 defected in SHP-2 binding had similar tumor suppressor function as F18, suggesting IRS-1 promote cancer cell growth by activating SHP-2 signaling. A synthetic peptide representing SHP-2 binding site was then used to screen a compound library. Preliminary analysis showed that 3 small molecular compounds were capable of inhibiting SHP-2 binding in vitro.
APPROVED FOR PUBLIC RELEASE