Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members.
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 (Brca1Delta11/Delta11) 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.
Shukla
Vivek
V
Genetics of Development and Disease Branch and Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. shuklav@mail.nih.gov
Coumoul
Xavier
X
Cao
Liu
L
Wang
Rui-Hong
RH
Xiao
Cuiying
C
Xu
Xiaoling
X
Andò
Sebastiano
S
Yakar
Shoshana
S
Leroith
Derek
D
Deng
Chuxia
C
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D019398:Genes, BRCA1; D016158:Genes, p53; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
D019313:BRCA1 Protein; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I