Background Significance: Type 2 diabetes (T2D) is a major health concern for the Qatari population and rates are expected to increase, impacting both children and adults. The disease is characterized by systemic hyperinsulinemia and hyperglycemia that causes debilitating and life-threatening effects. Strikingly, compared with people who do not have T2D, patients with T2D are more likely to be diagnosed with certain types of cancer, including breast and colon cancer. Breast cancer (BC) is ranked among the most frequently diagnosed cancers and a leading cause of death for Qataris. According to the National Cancer Strategy Qatar, incidence rates for all cancer types are projected to continue rising into the next decade. Hypothesis and Objectives: Various studies have posited that the link between T2D and risk for cancer may be attributed to disparities in access to care or lack of health awareness. But the most convincing line of evidence, showing that drugs that control glucose and insulin reduce the rate of cancer for T2D patients strongly suggests that unknown biological mechanisms are key. Our research plan will elucidate the molecular mechanisms linking T2D and BC and is shaped by the overarching hypothesis that the systemic diabetic condition promotes cancer cell transformation, growth and survival. Our objectives are: 1) ascertain how T2D promotes malignant cell transformation; and 2) test if mechanisms underlying cancer cell-specific metabolism, benefiting from T2D-associated hyperinsulinemia and hyperglycemia, modulate tumor cell response to targeted treatments; i.e., do they effect cancer drug resistance. Approach and Preliminary Data: The proposed research will investigate BC-derived cell lines, pre-clinical animal models and archived patient specimens. State-of-the-art genomic and molecular technologies will be used to elucidate and verify oncogenic signaling processes affected by T2D. Cancer is a disease dictated by somatic genome mutations. Recent studies conducted by Dr. Bollig-Fischer demonstrate how various mutation activated oncogenes cause metabolic transformation of pre-cancer cells and indicate how cancer cell-specific metabolism confers a growth advantage to burgeoning cancer in an environment of high glucose and hyperinsulinemia. Impact: First, a defined mechanistic link from T2D to BC can be used to rationalize the assignment of resources and bolstering of efforts in Qatar to improve cancer screening awareness and promote lifestyle changes to control diabetes. Second, we anticipate the discovery of evidence to inform us of the nature of cancer and how it relates to systemic biology. The results here will provide insights as to how treatments should be tailored to consider systemic pathology. This concept we are putting forth, that is to consider the whole of patient biology when treating cancer, represents a paradigm shift in the field of molecularly targeted treatments and personalized or precision medicine.
