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Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members

¹ Genetics of Development and Disease Branch and ² Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland and ³ Department of Cell Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy

Requests for reprints: Vivek Shukla, Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Building 10/9N105, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-594-3876; Fax: 301-480-1135; E-mail: shuklav{at}mail.nih.gov.

The breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1^11/11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. (Cancer Res 2006; 66(14): 7151-7)

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