Obesity is a contributing factor in 20% of all cancer deaths in women. Particularly, endometrial cancer (EC) incidence has risen steadily over the past two decades concomitant with the rise in global obesity rates. EC is a multifactorial disease, as both obesity and somatic driver mutations play causal roles. Mutations in the phosphoinositide 3-kinase (PI3K) pathway are present in over 80% of all EC. However, obesity or mutation alone is insufficient for EC pathogenesis. A major gap in knowledge is how genetic mutations alter EC risk in obese women, and evidence points towards impaired protein quality control as an important causal mechanism. Obesity results in systemic endoplasmic reticulum stress (ERS), which is triggered by the accumulation of unfolded proteins. If ERS cannot be achieved, the unfolded protein response induces cell death. The PI3K pathway antagonizes ERS and may promote cell survival under these conditions. For this project, we are studying the casual mechanistic relationship between obesity and PI3K pathway mutations in EC pathogenesis. Our central hypothesis is that obesity alone causes ERS in the normal uterus, resulting in cell death, but when a PI3K pathway mutation occurs in the endometrium of obese women this stress response does not happen, resulting in uncontrolled cell growth and cancer. We are exploring the mechanism using genetically engineered mouse models of EC.

Additional projects in the lab concern the role for mutations which have been so far unexplored. We are developing novel mouse models to understand the contributions of these mutations in disease progression. Particularly, we are investigating mutations which are found at higher rates in underrepresented patient populations. Notably, endometrial cancer mortality rate is doubled for African American patients compared to white patients within the Karmanos Cancer Institute patient population (more information here). Therefore, we hope to identify novel therapeutic targets so that equity in endometrial cancer treatments can be achieved.