HR and Genome Instability Early in HGSC: Role of Antioxidants
Abstract
High-grade serous carcinoma is the most common and aggressive histotype of epithelial ovarian cancer in women. Most HGSC arise in the fallopian tube epithelium (FTE). Nearly 25% of women who develop HGSC have inherited germ-line mutations in DNA repair genes (HR genes). HR genes are responsible for repairing double breaks in DNA strands (DSBs). DSBs are generated by internal factors such as spontaneous cell damage or oxidative damage generated by reactive oxygen species (ROS). ROS is produced by the mitochondria in the cell, and byproducts of fat metabolism and DNA synthesis. The fallopian epithelial cells are surrounded by stroma and an environment rich in ROS-inducing factors. For example, immune cells secrete growth factors, adipocytes secrete hormones and the ovary follicular fluid and hormones. The fallopian tube epithelial is bathed in a film of potentially damaging juices. Therefore, cells like the FTE have developed processes to protect their DNA, proteins, and other molecules necessary for cellular integrity and growth. One of these defense mechanisms is the antioxidant and scavenger metabolic system. Through appropriate environmental cues, these enzymes are poised to quench ROS, neutralize oxidized lipids, and scavenge foreign molecules like drugs, otherwise known as xenobiotics. Our preliminary data from studying fallopian tube cells closest to the ovary revealed they expressed high levels of certain ROS and xenobiotic scavenger/detoxifying enzymes. More importantly, when we looked at these genes in pre-cancerous lesions and metastatic chemotherapy-naïve ovarian cancer, we saw a decrease in their levels and they were re-expressed in recurrent and chemotherapy-resistant ovarian cancer. The mechanism of how fallopian tube cells use this defense strategy to protect their genome from damage is unknown. We also do not know how being in a rich hormonal environment affects their ability to respond to these oxidative stressors. Additionally, we do not know how the fallopian tube cells of women at the highest risk for developing ovarian cancer modify their oxidative stress response due to their inherent inability to repair their DNA breaks effectively. Our studies aim to better understand the biology of early disease and will include a detailed characterization of early pro-tumorigenic metabolic and oxidizing insults in FTE in high-risk women. Targeting metabolic and antioxidant rewiring as a chemoprevention option has not been fully explored in HGSCs. This proposal will assay HR mutant human FTE and HGSC from direct tumor biopsies and from FTE cell cultures and test how their activation of metabolic and antioxidant gene expression programs in response to internal metabolic demands and ROS, and external stressors like estrogen, may affect their ability to repair damaged DNA. This study will (1) identify targets of preventative intervention in women with genetic predisposition to ovarian cancer; (2) predict lesion progression from normal FTE to serous intraepithelial carcinoma (STIC) to HGSC and (3) understand how HGSC and other chemo-refractory cancer like Clear Cell carcinoma, co-opt the antioxidant program to become chemoresistance. I bring a unique perspective to the Ovarian Cancer Academy. My academic pursuits are tied into studying ovarian cancer disease predisposition using the fallopian tube epithelia as a model system. The cells are robust, undergo monthly cycles of proliferation and differentiation, exist in a DNA-toxic environment and many checkpoints to stymie uncontrolled cell growth. However, once these systems are bypassed, the cells become aggressive, grow rapidly, and eventually become resistant to chemotherapeutic treatment. By participating in the Academy, I will leverage my growing knowledge of fallopian tube cell biology and the scientific and clinical expertise of different Academy members and Leadership to develop innovative and impactful ways of answering these key questions. The ultimate succ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810072
Entities
People
- Sophia George
Organizations
- United States Army
- University of Miami