IGF Signaling in Breast Cancer
Over the past 15 years, the Yee laboratory has shown that the insulin-like growth factors (IGFs) play an important role in regulating breast cancer proliferation, survival, and metastasis. This work, along with other laboratories, has established that the type I IGF receptor (IGF1R) is a viable target for breast cancer therapy. Currently, there are at least 10 targeted anti-IGF drugs currently in clinical trial with several ongoing and proposed studies in breast cancer. In order to optimize the use of targeted therapies, tools must be developed to predict clinically relevant outcomes. For example, expression of estrogen receptor-alpha (ER) is an important predictor of response to anti-estrogen therapy but mere expression of ER alone is imperfect. Indeed, the first clinical trials are being performed that are designed to improve outcomes of anti-estrogen therapy based on gene expression profiling of tumors. Thus, the idea that gene expression profiling can reveal complex biologic and clinical phenotypes is now established.
These researchers will take advantage of a series of breast cancer cells they have created to develop gene expression signatures that correlate with IGF responsiveness. They hypothesize that expression of specific insulin receptor substrate (IRS) adaptor proteins link IGF1R to identifiable gene signatures and cancer phenotypes. To test this hypothesis, they will: develop gene expression profiles to predict phenotypes driven by IGF1R signaling; validate these signatures in vitro, in vivo, and in silico; and examine changes in gene expression signatures in vivo after anti-IGF1R therapy. Given the vast number of new drugs active in breast cancer, developing tools to personalize therapeutic decisions will be critical to continued success in decreasing breast cancer mortality. The long-term goal of this research is to use the discoveries made in the laboratory to optimize the use of anti-IGF drugs.