|
|
IGF-I and BRCA1: A New Feedback Loop?« Back to Volume 23, Issue 3, November 2007 - Table of Contents The growth hormone (GH)/insulin-like growth factor (IGF) system plays an important role in normal breast physiology and carcinogenesis. GH receptor (GH-R),1 IGF-I and type 1 IGF receptor (IGF1R) knock-out mice show impaired mammary ductal development from reduced proliferation in the terminal end buds.2 Conversely, transgenic mice over-expressing human (h)IGF-I or hIGF-II have reduced apoptosis and hence, delayed breast involution that normally occurs with the cessation of suckling and lactation.2 Further, dysregulated GH/IGF signaling has been implicated in breast cancer, a subject extensively reviewed elsewhere.3,4 Maor et al therefore sought to investigate the regulatory relationship between gene expression of IGF1R and the breast and ovarian cancer susceptibility gene (BRCA1), a major tumor suppressor in breast carcinogenesis. As indicated by Western immunoblotting and RT-PCR, BRCA1 expression was induced by treating MCF-7 breast cancer cells in vitro with IGF-I or IGF-II. Using BRCA1 promoter-luciferase reporter constructs, IGF-I treatment of MCF-7 and BRCA1-null HCC1937 breast cancer cells significantly enhanced promoter activity of the full-length BRCA1 promoter but not a minimal BRCA1 promoter deletion construct that lacks binding sites of the transcription factor Sp1. Drosophila-derived, Sp1-null Schneider cells were then co-transfected with the BRCA1 reporter construct and an Sp1 expression vector, which led to an almost 12-fold increase in BRCA1 promoter activity. Conversely, Mithramycin A, an Sp1-inhibitor, inhibited the IGF-I-stimulated BRCA1 expression and promoter activity in MCF-7 cells. Likewise, siRNA against Sp1 markedly reduced BRCA1 protein levels in MCF-7 cells. Binding of Sp1 to the BRCA1 promoter, as indicated by chromatin immunoprecipitation (ChIP) assay, was enhanced by IGF-I treatment of the MCF-7 cells. Finally, transfection of an anti-BRCA1 siRNA, versus a scrambled siRNA, increased the proportion of MCF-7 cells arrested at SubG0 and reduced those at the G2/M phase in response to IGF-I treatment. The authors concluded that BRCA1 is a novel downstream target of IGF1R signaling. IGF1R signaling induces BRCA1 gene expression via the Sp1 transcription factor, and BRCA1 gene silencing stunted IGF-stimulated cell cycle progression. Thus, they inferred that aberrant IGF signaling may lead to dysregulated BRCA1 expression during breast cancer pathogenesis. Maor S, Papa MZ, Yarden RI, et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res. 2007;39:179–85. Editor’s CommentBRCA1 is major tumor suppressor involved in breast carcinogenesis, including both somatic dysfunction and increased familial cancer risk due to germline inactivating mutations. Normally, BRCA1 plays a role in genomic stabilization, inducing cell cycle arrest and DNA repair in response to DNA damage.5 BRCA1 acts as transcription factor, interacting with co-repressors and co-activators, to inhibit expression of growth-promoting genes and stimulate expression of cell cycle arrest and DNA repair genes, DNA damage inducible genes and interferon inducible genes.6 As shown by the same authors as the current paper, one of the genes whose transcription is repressed by BRCA1 is IGF1R.7 Thus, their 2 findings may form a feedback loop (Figure), whereby IGF1R signaling induces BRCA1 transcription which in turn represses IGF1R transcription. Adda Grimberg, MD
References - (linked to
|
Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
)