PROJECT SUMMARY/ABSTRACT Research Project: Excess body weight is a contributing factor in up to 20% of all cancer deaths in women. In particular, 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 PI3K pathway mutation alone are 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 causes systemic endoplasmic reticulum stress (ERS), which is triggered by the accumulation of unfolded proteins. If proteostasis cannot be achieved, the unfolded protein response induces cell death. Due to increased aromatase activity, obesity creates an “unopposed estrogen” phenotype, which drives EC and results in ERS in the uterus. The PI3K pathway antagonizes ERS and may promote cell survival under these conditions. Here, I propose to study the casual mechanistic relationship between obesity and PI3K pathway mutations in EC pathogenesis. My 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. In this application, I propose to 1) Determine the relationship between PI3K mutation and ERS in the endometrium 2) Characterize the role of estrogen-induced ERS in EC 3) Determine the role for metabolism-induced ERS in EC prevention. Career Goals: My career will be focused on cancer research. In graduate school, I developed novel cancer therapeutics targeting nucleotide biosynthesis under the guidance of Dr. Larry Matherly. As an American Cancer Society Postdoctoral Fellow in Dr. Ronald Chandler’s lab, I uncovered the mechanism by which common somatic mutations in the endometrial epithelium result in myometrial invasion in EC. My goal is to secure a tenure-track faculty position at a leading cancer research institution, and to develop a research program exploring the relationship between obesity and mutation in EC pathogenesis to identify targets for active preventative intervention. Career Development and Environment: The K99/R00 award will secure the necessary time and training to develop my career as a successful independent investigator. My mentors will be Drs. Ronald Chandler, Jose Teixeira and Victoria Bae- Jump, experts in the field of gynecologic oncology. Activities planned will focus on gaining new expertise in obesity research. Michigan State University and the Van Andel Research Institute are the ideal location for this training, being home to many experts in gynecologic oncology, cancer metabolism, mouse modeling and bioinformatics. The Michigan Nutrition Obesity Research Center will provide additional education and training in the fields of metabolism and obesity research.

PROJECT NARRATIVE Endometrial cancer incidence is increasing 1.3% year over year in the United States as a consequence of the obesity pandemic. A major gap in knowledge is how genetic mutations alter endometrial cancer risk in obese women, and evidence points towards impaired protein quality control as an important causal mechanism. This proposal addresses the goals of the NCI Strategic Plan to identify and characterize risk factors for cancer, to study how cellular stress responses contribute to cancer development and progression and to develop and test new approaches for cancer prevention through studies that will determine if recurrent phosphoinositide 3-kinase (PI3K) pathway mutations reshape protein quality control mechanisms in obese women at-risk for endometrial cancer.