The critical role of GRP78 for endometrial cancer development and progression

Lin-Liu, Yvonne

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States and is associated with obesity. Exactly how obesity leads to the development of endometrial cancer is not known. Obesity, however, prompts cells to increase protein production, sometimes overwhelming the cell's protein processing and folding machinery. This results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), all orchestrated by the glucose regulated protein-78 (GRP78) as the cell attempts to compensate for the excess protein. While this phenomenon protects normal cells, dysregulation of these events has been identified in human cancers. In fact, we identified both GRP78 upregulation in endometrioid cancers, as well as ER stress induction in visceral adipocytes. We then discovered that when we created a new transgenic mouse model with a conditional biallelic deletion of both Grp78 and the tumor suppressor gene (Pten), GRP78, the same regulator of obesity-associated ER stress induction, was necessary for endometrial cancer development. These findings prompted me to hypothesize that GRP78 is a critical effector of endometrial cancer development through its ability to promote endometrial cancer cell proliferation and growth, while simultaneously blocking apoptosis. To study this hypothesis, this proposal aims to 1) characterize the role of GRP78 in endometrial cancer development and progression from benign endometrium to frank cancer, 2) characterize tumor cell growth, proliferation, and apoptosis in the endometrium and adjacent visceral adipocytes in our novel transgenic mouse model of de novo endometrial cancer development after dietary- and pharmacologic- induction of GRP78, and 3) assess the impact of therapeutically targeting GRP78 on endometrial cancer cell growth and apoptosis. The principal investigator is a physician-scientist with the long- term goal of establishing herself as an independent translational scientist in endometrial cancer biology with a unique focus on GRP78, ER stress, and dysregulated molecular mechanisms responsible for cancer development. The career development program of this proposal integrates intensive laboratory-based research training under the direct scientific mentorship of Dr. Amy Lee, a pioneer in the field of ER stress and GRP78 and the translational co-mentorship of Dr. Debu Tripathy an internationally renowned leader in breast medical oncology and early drug development. The committed mentorship Dr. Lin will have in her research endeavors will be complemented by institutional seminars and didactics to help her develop into an independent investigator and active contributor to the scientific community of physician-scientists.

Public Health Relevance

Increasing rates of obesity are leading to increasing rates of endometrial cancer, affecting nearly 50,000 women annually in the United States. This proposal represents the first comprehensive evaluation of the critical role GRP78 has in endometrial cancer development and evaluates GRP78 as a therapeutic candidate to reduce the public health burden of this increasingly common cancer. PUBLIC HEALTH RELEVANCE: Increasing rates of obesity are leading to increasing rates of endometrial cancer, affecting nearly 50,000 women annually in the United States. This proposal represents the first comprehensive evaluation of the critical role GRP78 has in endometrial cancer development and evaluates GRP78 as a treatment candidate to reduce the public health burden of this increasingly common cancer.