Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members

Vivek Shukla, Xavier Coumoul, Liu Cao, Rui Hong Wang, Cuiying Xiao, Xiaoling Xu, Sebastiano Andò, Shoshana Yakar, Derek LeRoith, Chuxia Deng

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7151-7157
Number of pages7
JournalCancer Research
Volume66
Issue number14
DOIs
StatePublished - Jul 15 2006

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Neoplasm Genes
Somatomedins
Breast Neoplasms
Histones
Premature Aging
Biological Phenomena
RNA Interference
Epigenomics
Chromatin
Cultured Cells
Carcinogenesis
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. / Shukla, Vivek; Coumoul, Xavier; Cao, Liu; Wang, Rui Hong; Xiao, Cuiying; Xu, Xiaoling; Andò, Sebastiano; Yakar, Shoshana; LeRoith, Derek; Deng, Chuxia.

In: Cancer Research, Vol. 66, No. 14, 15.07.2006, p. 7151-7157.

Research output: Contribution to journalArticle

Shukla, Vivek ; Coumoul, Xavier ; Cao, Liu ; Wang, Rui Hong ; Xiao, Cuiying ; Xu, Xiaoling ; Andò, Sebastiano ; Yakar, Shoshana ; LeRoith, Derek ; Deng, Chuxia. / Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. In: Cancer Research. 2006 ; Vol. 66, No. 14. pp. 7151-7157.
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