Abstract
A significant volume of clinical and epidemiological data provides support to the concept that insulin and the insulin receptor (INSR) have an important role in breast cancer. Tumor suppressor p53 is the most frequently mutated molecule in human cancer. The present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells. In addition, the study was designed to investigate the mechanism of action of p53 in the context of INSR gene regulation. The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor (IGF1R) or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression. Data indicate that the INSR gene constitutes a target for p53 action. Wild-type p53 stimulated INSR promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53. Mutant p53 strongly stimulated INSR promoter. Furthermore, p53 directly binds to the INSR promoter in cells with a disrupted IGF1R. Combined, our results identified complex functional and physical interactions between p53 and the INSR pathway. The implications of the p53-INSR interplay in breast cancer needs to be further investigated.
Highlights
The insulin/insulin-like growth factors (IGFs) create an hormonal network responsible for the regulation of important physiological events throughout life [1,2,3]
While the relative contribution of the insulin receptor (INSR) and IGF1 receptor (IGF1R) signaling pathways to the development of a malignant www.oncotarget.com www.oncotarget.com phenotype has been a controversial issue for many years, a mounting volume of experimental, clinical and epidemiological data provides strong support to the notion that insulin signaling is central to cancer etiology [34]
The present study was aimed at evaluating the hypothesis that tumor suppressor p53 governs the expression and activation of the INSR gene in breast cancer cells
Summary
The insulin/insulin-like growth factors (IGFs) create an hormonal network responsible for the regulation of important physiological events throughout life [1,2,3]. The biological information conveyed by this complex system governs multiple metabolic, endocrine, nutritional and growth processes [4,5,6,7]. This growth factor system plays key developmental roles at each stage of life, from early in utero phases until old age [8, 9]. A number of non-classical insulin-like molecules have been identified in recent years, including the insulin receptor-related receptor (IRR), insulin-IGF1 hybrid receptor and a number of IGFBPrelated proteins [14, 15]. The physiological roles of these new members, for the most part, are yet to be elucidated
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