published_or_final_version / abstract / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Clinical Oncology / Master / Master of Philosophy

Choi, Pui Wah. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 202-232). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

Advancements in medicine and technology have led to an increasing number of cancer survivors. The development of a second primary cancer is one of the most severe sequelae of a cancer diagnosis, particularly for cancers that lack an effective screening tool as with ovarian cancer. Breast and ovarian cancer are major causes of morbidity and mortality in women; in the U.S., breast cancer has the highest incidence in women and ovarian cancer is the most fatal of gynecological cancers. Further, these two cancers have been found to co-occur. Along with possible treatment effects of the first cancer, shared risk factors, shared genetics, and interactions between these two have been hypothesized to contribute to their co-occurrence. Research on shared risk factors for second cancers is lacking and being able to identify potentially modifiable factors associated with second primary cancer could improve clinical recommendations for cancer survivors. Therefore, this dissertation examined risk factors for the development of double primary breast and ovarian cancer (DPBOC) in three parts 1) a comprehensive review of the literature to identify studies assessing risk factors for DPBOC, 2) a case-control study assessing the association between three potentially-modifiable risk factors (oral contraceptive (OC) use, parity, and breastfeeding), and risk of second primary ovarian cancer following breast cancer (BR-OV), second primary breast cancer following ovarian cancer (OV-BR), single primary ovarian cancer (OV), and single primary breast cancer (BR), and 3) a cohort study assessing OC use, parity, and breastfeeding and risk of BR-OV, OV, and BR. The comprehensive review identified few studies assessing epidemiologic risk factors for the development of DPBOC and most of the findings were not statistically significant. The majority of studies focused on treatment of breast cancer and risk of second primary ovarian cancer. While most of the findings on chemotherapy, radiotherapy, and Tamoxifen were heterogeneous and lacked statistical significance, hormone therapy for breast cancer may be associated with an increased risk of second primary ovarian cancer. The majority of studies on genetic risk factors for DPBOC looked at BRCA1/2 mutations or a crude measure of family history. Both BRCA1/2 and family history were consistently associated with risk of DPBOC, but studies varied on the extent of this risk due to differences in study design, exposure and outcome definition, and statistical power. No studies were identified examining DNA methylation and risk of DPBOC. The case-control study used data from the three clinic-based sites of the Breast Cancer Family Registry (BCFR) which consisted of women from breast and ovarian cancer families. We observed an inverse association with both OC use (OR=0.38, 95% CI: 0.22, 0.60) and breastfeeding (OR=0.52, 95% CI: 0.31, 0.87) and risk of DPBOC, but a positive association with parity (≥2 full-term pregnancies: OR=5.78, 95% CI: 2.82, 14.58), regardless of diagnosis order (BR-OV or OV-BR). We found similar associations for our OV and BR outcomes as well. When we examined differences between high and average risk women (using BRCA1/2 mutation status and predicted lifetime risk of breast or ovarian cancer), the inverse association with OC use only remained in women at average risk while the inverse association with breastfeeding only remained in women at high risk. As the positive association with parity and all of our outcomes disagreed with our hypothesis we conducted several sensitivity analyses to explore this finding. Survivor bias may have influenced our results as we observed differences in our findings between cases diagnosed ≤2 or ≤5 years before the baseline interview (pseudo-incident) and cases diagnosed >2 or >5 years before the baseline interview (prevalent). Specifically, the inverse association with OC use and all of our outcomes, and the positive association with parity and all of our outcomes were attenuated in the pseudo-incident group. To address concerns of selection and information bias in our case-control study, we conducted a cohort study using data from The Breast Cancer Prospective Family Study Cohort (ProF-SC). In contrast to our case-control findings, we observed a suggestive positive association between OC use and risk of BR-OV (HR=1.62, 95% CI: 0.91, 2.90) which became stronger in women at high risk, and an inverse association between having two or more full-term pregnancies compared to nulliparous and risk of BR-OV (HR=0.47, 95% CI: 0.22, 0.97) which did not vary by underlying risk of breast and ovarian cancer. However, our BR-OV results may have similarly been influenced by survivor bias as we observed differences in our results between our pseudo-incident and prevalent BR-OV cases; the association between OC use and BR-OV only remained in the prevalent cases. In summary, the results of this dissertation highlight the methodological challenges in the study of second primary cancers and the importance of considering survivor bias in a cohort of cancer survivors being followed for second cancers. Further, our results are suggestive of a discordant effect of OC use on first primary versus second primary ovarian cancer which should be explored in future studies.

Ovarian cancer is the 5th leading cause of cancer death in women in the United States and is the most fatal gynecological malignancy. High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer largely due to the rapid metastasis throughout the peritoneum (abdominal cavity wall and organ lining). Metastatic spread of ovarian cancer usually occurs before diagnosis and can lead to bowel obstruction, organ failure, ascites, cachexia, infection and sepsis, and pulmonary embolism all causing death. Current methods to detect early stage ovarian cancer do not increase overall survival. A better understanding of the metastatic ability of ovarian cancers and the mechanism of cancer cell dissemination are critical to the development of new treatments for this devastating disease. In particular, investigation of pathways that affect early metastasis may indicate treatments that will lower disease burden and may suggest biomarkers of recurrent and/or chemotherapy resistant disease. Notch3 expression correlates with worse prognosis, chemotherapy resistance, and increased tumorigenic cell behaviors in HGSC. Here, we demonstrate that Notch3 acts to promote early stages of metastasis in a model of HGSC using the murine ID8 IP2 ovarian surface epithelial cell line. ID8 IP2 cells have little to no endogenous Notch3 expression and model metastatic disease when introduced intraperitoneally. We investigated the role of Notch3 by ectopically expressing the intracellular domain of murine Notch3 to induce constitutive Notch3 signaling in ID8 IP2 cells and verified Notch signal activation by target gene assessment. Induction of Notch3 signaling in ID8 IP2 reduced survival and accelerated disease burden, as measured by ascites accumulation, after intraperitoneal introduction of cells into nude mice. We interrogated downstream targets in Notch3 activated cells by RNA-Seq and found that Notch3 induced a significant enrichment of adhesion and extracellular matrix pathways. Notch3 active cells showed increased ITGA1 expression and increased adhesion on collagens I and IV in vitro, suggesting that increased adhesion to collagen-rich peritoneal surfaces drives the observed increase in tumor burden. Notch3 active cells showed reduced migration on surfaces coated with multiple types of extracellular matrix and no detectable increase in invasion through extracellular matrix, indicating that Notch3 effects may be specific to the initial adhesion of tumor cells and not the later stages of metastasis. These results demonstrate that Notch3 upregulates the expression of specific adhesion genes in ovarian cancer cells and this promotes increased attachment to the collagen-rich extracellular matrix. The implications of this study are that oncogenic Notch signal activation, as documented in human disease, may promote dissemination and metastasis of primary and/or recurrent HGSC by increasing attachment to the peritoneal lining.

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Biological Sciences / Master / Master of Philosophy

published_or_final_version / Obstetrics and Gynaecology / Master / Master of Philosophy