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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Available from: Haim Werner, Oct 05, 2015
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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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    ABSTRACT: IGF1R plays an important role in protection from apoptosis, regulation of cell growth, differentiation and oncogenic transformation. IGF1R aberrations lead to intrauterine and postnatal growth failure, microcephaly, mental retardation and deafness. High levels of IGF1R are detected in a diversity of human tumors. IGF1R gene transcription is controlled by complex interactions involving DNA-binding and non DNA-binding transcription factors. This review highlights selected examples of a series of tumor suppressors, including the breast cancer gene-1 (BRCA1), p53, the Wilm’s tumor protein-1 (WT1) and the von Hippel-Lindau gene (VHL), whose mechanisms of action involve regulation of IGF1R gene expression. IGF1R gene transcription is also dependent on the presence of stimulatory nuclear proteins, including zinc-finger protein Sp1, EWS-WT1, E2F1, Krüppel-like factor-6 (KLF6), high-mobility group A1 (HMGA1), and others. Loss-of-function of tumor suppressor genes, usually caused by mutations, may result in non-functional proteins unable to control IGF1R promoter activity. Impaired regulation of the IGF1R gene is linked to defective cell division, chromosomal instability and increased incidence of cancer.
    Growth Hormone & IGF Research 08/2014; 24(4). DOI:10.1016/j.ghir.2014.03.006 · 1.41 Impact Factor
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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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    Frontiers in Endocrinology 05/2014; 5. DOI:10.3389/fendo.2014.00076
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    • "So far, the scientific community is convinced, without data to the contrary, that the IGF-1 system is not, by its nature, oncogenic. The activated receptors are not genotoxic nor do they cause DNA mutations or any other kind of DNA damage [61]. However, they do severely affect the progress of the cell cycle, pushing cells to proliferate at an alarming rate, once their regulation is influenced, like in cases of cancer. "
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