# Does obesity influence protein quality control in endometrial cancer?

> **NIH NIH K99** · MICHIGAN STATE UNIVERSITY · 2022 · $118,228

## Abstract

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...

## Key facts

- **NIH application ID:** 10376805
- **Project number:** 5K99CA252152-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** MICHAEL R WILSON
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $118,228
- **Award type:** 5
- **Project period:** 2021-04-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376805

## Citation

> US National Institutes of Health, RePORTER application 10376805, Does obesity influence protein quality control in endometrial cancer? (5K99CA252152-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376805. Licensed CC0.

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