Insulin-like Growth Factor-I Controls BRCA1 Gene Expression through Activation of Transcription Factor Sp1

Abstract

The insulin-like growth factors (IGFs) have a central role in mammary gland growth and differentiation as well as in breast cancer development. The BRCA1 gene encodes a pleiotropic protein that functions as a transcription factor. Germline BRCA1 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms. Several lines of evidence led us to hypothesize that there is a functional interaction between the BRCA1 and IGF-I systems relevant to breast cancer biology. The present study tested the notion that BRCA1 gene expression is regulated by the IGF-I signaling pathway. Results of Western immunoblotting and RT-PCR analyses show that IGF-I stimulates BRCA1 protein and mRNA levels. Transient transfection experiments using BRCA1 promoter-luciferase reporter constructs reveal that IGF-I enhances BRCA1 promoter activity, suggesting that the effect of IGF-I is mediated at the transcriptional level. In addition, we provide evidence that the Sp1 zinc-finger protein is directly involved in BRCA1 gene transactivation. Combined, our data suggests that, at least part of the biological actions of IGF-I in mammary gland cells may be mediated through BRCA1. Dysregulated BRCA1 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis.

Keywords

IGF-I - IGF-I receptor - BRCA1 - breast cancer - transcription - Sp1

References

• 1 Surmacz E. Function of the IGF-I receptor in breast cancer.  J Mamm Gland Biol Neoplasia. 2000;  5 95-105
• 2 Yee D, Lee AV. Crosstalk between the insulin-like growth factors and estrogens in breast cancer.  J Mamm Gland Biol Neoplasia. 2000;  5 107-115
• 3 Werner H, LeRoith D. The role of the insulin-like growth factor system in human cancer.  Adv Cancer Res. 1996;  68 183-223
• 4 Osborne CK, Clemmons DR, Arteaga CL. Regulation of breast cancer growth by insulin-like growth factors.  J Steroid Biochem Mol Biol. 1990;  37 805-809
• 5 Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.  The Lancet. 1998;  351 1393-1396
• 6 LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT. Molecular and cellular aspects of the insulin-like growth factor I receptor.  Endocrine Rev. 1995;  16 143-163
• 7 Baserga R. The IGF-I receptor in cancer research.  Exp Cell Res. 1999;  253 1-6
• 8 Sell C, Rubini M, Rubin R, Liu J-P, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor.  Proc Natl Acad Sci USA. 1993;  90 11217-11221
• 9 Heidenreich KA, Zeppelin T, Robinson LJ. Insulin and insulin-like growth factor I induce c-fos expression in postmitotic neurons by a protein kinase C-dependent pathway.  J Biol Chem. 1993;  268 14663-14670
• 10 Dupont J, Fernandez AM, Glackin CA, Helman L, LeRoith D. Insulin-like growth factor I (IGF-I)-induced twist expression is involved in the anti-apoptotic effects of the IGF-I receptor.  J Biol Chem. 2001;  276 26699-26707
• 11 Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA. et al . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.  Science. 1994;  266 66-71
• 12 Wang Q, Zhang H, Fishel R, Greene MI. BRCA1 and cell signaling.  Oncogene. 2000;  19 6152-6158
• 13 Yang X, Lippman ME. BRCA1 and BRCA2 in breast cancer.  Breast Cancer Res Treat. 1999;  54 1-10
• 14 Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, Peretz T. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.  Am J Hum Genet. 1997;  60 505-514
• 15 Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC, Jensen RA. Growth retardation and tumour inhibition by BRCA1.  Nature Gen. 1996;  12 298-301
• 16 Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C. et al . BRCA1 mutations in primary breast and ovarian carcinomas.  Science. 1994;  266 120-122
• 17 Idelman G, Glaser T, Roberts Jr CT, Werner H. WT1-p53 interactions in IGF-I receptor gene regulation.  J Biol Chem. 2003;  278 3474-3482
• 18 Arizti P, Fang L, Park I, Yin Y, Solomon E, Ouchi T, Aaronson SA, Lee SW. Tumor suppressor p53 is required to modulate BRCA1 expression.  Mol Cell Biol. 2000;  20 7450-7459
• 19 Werner H, Bach MA, Stannard B, Roberts Jr CT, LeRoith D. Structural and functional analysis of the insulin-like growth factor I receptor gene promoter.  Mol Endocrinol. 1992;  6 1545-1558
• 20 Xu C-F, Chambers JA, Solomon E. Complex regulation of the BRCA1 gene.  J Biol Chem. 1997;  272 20994-20997
• 21 Yee D, Jackson JG, Von Hoff DD, Ravdin PM. Case report: use of insulin-like growth factor-I gene expression to distinguish between breast and ovarian cancer.  Am J Med Sci. 1994;  307 108-111
• 22 Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin G-Y, Abel KJ, Weber BL, Chodosh LA. The developmental pattern of BRCA1 expression implies a role in differentiation of the breast and other tissues.  Nature Gen. 1995;  11 17-26
• 23 Satterwhite DJ, Matsunami N, White RL. TGF-beta1 inhibits BRCA1 expression through a pathway that requires pRb.  Biochem Biophys Res Commun. 2000;  276 686-692
• 24 Vaughn JP, Davis PL, Jarboe MD, Huper G, Evans AC, Wiseman RW, Berchuck A, Iglehart JD, Futreal PA, Marks JR. BRCA1 expression is induced before DNA synthesis in both normal and tumor-derived breast cells.  Cell Growth Diff. 1996;  7 711-715
• 25 Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.  Nature Gen. 2002;  30 285-289
• 26 Pore N, Liu S, Shu HK, Li B, Haas-Kogan D, Stokoe D, Milanini-Mongiat J, Pages G, O'Rourke DM, Bernhard E, Maity A. Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism.  Mol Cell Biol. 2004;  15 4841-4853
• 27 Kitadai Y, Yasue W, Yodozaki H, Kuniyasu H, Haruma K, Kajiyama G, Tahara E. The level of transcription factor Sp1 is correlated with the expression of EGF receptor in human gastric carcinomas.  Biochem Biophys Res Commun. 1992;  189 1342-1348
• 28 Abramovitch S, Glaser T, Ouchi T, Werner H. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene.  FEBS Lett. 2003;  541 149-154
• 29 Maor SB, Abramovitch S, Erdos MR, Brody LC, Werner H. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.  Mol Gen Metab. 2000;  69 130-136
• 30 Abramovitch S, Werner H. Functional and physical interactions between BRCA1 and p53 in transcriptional regulation of the IGF-IR gene.  Horm Metab Res. 2003;  35 758-762
• 31 Seeger H, Huober J, Wallwiener D, Mueck AO. Inhibition of human breast cancer cell proliferation with estradiol metabolites is as effective as with tamoxifen.  Horm Metab Res. 2004;  36 277-280
• 32 Fortunati N, Catalano MG. Sex hormone-binding globulin (SHBG) and estradiol cross-talk in breast cancer cells.  Horm Metab Res. 2006;  38 236-240

Correspondence