TY - JOUR
T1 - Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members
AU - Shukla, Vivek
AU - Coumoul, Xavier
AU - Cao, Liu
AU - Wang, Rui Hong
AU - Xiao, Cuiying
AU - Xu, Xiaoling
AU - Andò, Sebastiano
AU - Yakar, Shoshana
AU - LeRoith, Derek
AU - Deng, Chuxia
PY - 2006/7/15
Y1 - 2006/7/15
N2 - 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 (Brca1Δ11/Δ11) 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 tumor-igenesis and aging.
AB - 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 (Brca1Δ11/Δ11) 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 tumor-igenesis and aging.
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U2 - 10.1158/0008-5472.CAN-05-4570
DO - 10.1158/0008-5472.CAN-05-4570
M3 - Article
C2 - 16849561
AN - SCOPUS:33746912264
VL - 66
SP - 7151
EP - 7157
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 14
ER -