Gynecological tissue homeostasis and tumorigenesis studies using mouse models

Abstract

Gynecological cancers present a tremendous disease burden worldwide. Endometrial cancer, the most common gynecological malignancy, is predominantly a disease of deranged glandular function. The mechanisms by which known environmental risk factors influence the mutational profile of endometrial cancer are poorly understood. Non-HPV vulvar cancer, on the other hand, is a very rare gynecological malignancy of vii PUBLIC ABSTRACT Cancer is caused by genetic mutations. These mutations harm our DNA and prevent cells from functioning normally. Mutations can be inherited from parents. They can also be caused by exposure to harmful agents such as toxic chemicals or radiation. More often than not, however, mutations that cause cancer occur spontaneously over the course of our lifetimes. While many mutations do not cause disease, certain mutations under certain conditions can give rise to cells that behave in a way that facilitates their growth and survival, but harms the organism (human) as a whole. A key objective of cancer research is to identify the harmful mutations so that therapies can be developed to stop cells with harmful mutations while leaving normal, healthy cells alone. In this thesis, data are presented on endometrial cancer and vulvar cancer. Endometrial cancer, or uterine cancer, is the most common gynecological cancer. While environmental risk factors including obesity and high-dose estrogen are known to be associated with endometrial cancer, scientists still do not entirely understand how they contribute to the accumulation of mutations in uterine cells. On the other hand, vulvar cancer is very rare and little is known about how it forms. To identify the mutations giving rise to these two distinct gynecological cancers, I designed different models to permit the identification of mutations responsible for their formation. I hope these findings will contribute to improved therapies and patient care. viii TABLE OF CONTENTS LIST OF FIGURES .