The Regulation of Insulin Receptor/insulin-like Growth Factor Receptor Ratio, an Important Factor for Breast Cancer Prognosis, by TRIP-Br1

Abstract Much higher risk of cancer is observed in patients with diabetes. Insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are well-known targets in cancer research as well as diabetes treatment. Interestingly, a recent study proposed that the IR/IGF1R ratio is an important factor in breast cancer prognosis. Women with a higher IR/IGF1R ratio showed poor breast cancer prognosis and hyperinsulinemia. Here, we propose a novel mechanism by which the oncogenic protein TRIP-Br1 renders breast cancer cells to have a higher IR/IGF1R ratio by positively and negatively regulating IR and IGF1R expression at the protein level, respectively. TRIP-Br1 plays various cellular roles, one of which is as an adaptor protein. Our data revealed that TRIP-Br1 suppresses ubiquitin/proteasome-mediated IR degradation without directly interacting with IR. Meanwhile, TRIP-Br1 directly interacts with both IGF1R and NEDD4-1 E3 ubiquitin ligase, and TRIP-Br1/NEDD4-1 degrades IGF1R via the ubiquitin/proteasome system. Animal experiments indicated that TRIP-Br1 enhanced tumor progression, where a high IR/IGF1R ratio was detected. Furthermore, IR silencing elevates IGF1R expression, resulting in a lower IR/IGF1R ratio. Our extended study showed a similar effect of TRIP-Br1 on the IR/IGF1R ratio in insulin-deficient mice mimicking patients with diabetes, confirming the strong relationship between breast cancer and diabetes. In conclusion, this study provides invaluable information on the regulatory mechanism of how breast cancer cells acquire a higher IR/IGF1R ratio.