IGF-1 and BRCA1 signaling pathways in familial cancer

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: .
The Lancet Oncology (Impact Factor: 24.69). 12/2012; 13(12):E537-44. DOI: 10.1016/S1470-2045(12)70362-5
Source: PubMed


The insulin-like growth factor (IGF) system has a direct effect on cellular proliferation and survival, and interacts with genetic and environmental factors implicated in causing cancer. Experimental, clinical, and epidemiological evidence show that the IGF signalling pathways are important mediators in the biochemical and molecular chain of events that lead from a phenotypically normal cell to one harbouring neoplastic traits. BRCA1 and BRCA2 have an important role in the development of hereditary and sporadic breast and ovarian cancer. Recent evidence suggests that risk of cancer conferred by BRCA mutations can be modified by genetic and environmental factors, including ambient concentrations of IGF-1 and polymorphisms in IGF system components. This Review addresses interactions between the IGF and BRCA1 signalling pathways, and emphasises the convergence of IGF-1-mediated cell survival, proliferative pathways, and BRCA1-mediated tumour protective pathways. Understanding the complex interactions between these signalling pathways might improve our understanding of basic molecular oncology processes and help to identify new molecular targets, predictive biomarkers, and approaches for optimising cancer therapies.

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    • "In addition to breast cancer, BRCA1 was identified as a transcriptional repressor of the IGF1R gene in prostate and endometrial cancer cells [45] [46]. AKT, a downstream target of IGF1, was shown to regulate BRCA1 stability [39]. Finally, studies revealed that IGF1 and IGF2 regulate BRCA1 levels at the transcriptional level [47] "
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    • "As discussed above, our studies provided evidence for functional and physical interactions between the IGF signaling pathways and tumor suppressors p53 and BRCA1. We demonstrated that IGF1R gene transcription rate is dependent on a number of stimulatory nuclear proteins and is also modulated by negative transcriptional regulators, including p53/p63/p73 (45, 75) and BRCA1 (46–50). The level of expression of the IGF1R gene is ultimately determined by complex interactions between stimulatory and inhibitory transcription factors. "
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