Mechanisms in IGF-ll induced Chemoresistance and Mitochondrial regulation in TNB

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PROJECT SUMMARY (See instructions): African American (AA) women have a lower incidence of breast cancer, however they experience a higher mortality rate. Moreover, AA women are associated with worse outcomes when treated with currently available adjuvant chemotherapy. Triple negative breast cancer (TNBC) is a subgroup of basal-like breast cancer that accounts for nearly 15-20% of all BC forms, however, it represents 45% of all BC observed in AA patients. TNBC tumors are estrogen-independent, have a very aggressive clinical behavior and are resistant to currently available therapy. Thus, development of TNBC results in a reduced disease-free survival period and increased mortality of AA breast cancer (BC) patients. Addressing this survival disparity will depend upon identification of contributing biological factor(s) that can be translated into new treatments. We are responding to RFA-MD-11-002 to address the theme "The pathways and mechanisms by which biologic and non-biologic determinants contribute to or influence minority health or health disparities". Our breast cancer research team (LLU-COE NIMHD) demonstrated that IGF-II activates several signaling pathways to increase survival proteins that regulate the mitochondria inducing chemoresistance in BC cells. These effects were reversed by resveratrol treatment (RSV) and we determined that IGF-II was inhibited by RSV causing mitochondrial cell death. We also showed that breast tumors from AA express significantly higher levels of IGF-II, survival proteins and higher activation of the IGF signaling pathways than Caucasian women. Thus, we hypothesize that since IGF-II promotes chemoresistance in BC cells, expression of IGF-II in tumors will promote chemoresistance, contributing to the survival disparity observed among AA patients. This hypothesis will be tested by four Specific Aims: 1: Demonstrate that IGF-II expression in TNBC cell lines induces chemoresistance, 2: Determine which mitochondrial proteins and signaling pathways mediate chemoresistance. Aim 3: Develop a mouse model to demonstrate that IGF-ll-producing breast tumors are chemoresistant and Aim 4: Develop a pilot study to assess the effect of RSV on the levels of circulating IGFII, and survival proteins in healthy African American women in the Inland Empire. Successful completion of the proposed studies by our highly synergistic team will have a significant impact in the treatment and survival of TNBC patients because it will validate IGF-II as a biomarker for chemoresistance, will provide new IGF downstream targets to inhibit chemoresistance and will validate new biomarkers to assess response to chemotherapy (chemo-responsiveness). Consequently, improved treatment will contribute to reduced mortality, eliminating the survival disparity observed among TNBC patients.