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The breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. M ice homozygous for a targeted deletion of full-length BRCA1 (Brca1D11/D11) 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.

Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members / Shukla, V; Coumoul, X; Cao, L; Wang, Rh; Xiao, C; Xu, X; Ando', Sebastiano; Yakar, S; Leroith, D; Deng, C.. - In: CANCER RESEARCH. - ISSN 0008-5472. - 66:14(2006), pp. 7151-7157.

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