S100A1 and nectin 4 biomarkers in ovarian cancer.

Abstract

This doctoral thesis focuses on the use of protein biomarkers for ovarian cancer detection, diagnosis, and determination of prognosis. Ovarian cancer is frequently detected after metastasis has occurred; at this point, it is difficult to remove all the residual disease, resulting in poor survival. We hypothesize that discovering and validating novel biomarkers will allow for more sensitive, specific tests which may allow earlier detection and increase survival for women diagnosed with ovarian cancer. Work presented in this dissertation focuses on two biomarkers of ovarian cancer, S100A1 and nectin 4. S100A1 is a calcium binding protein involved in several cellular processes, including metabolism, regulation of cell cytoskeleton components, and the contractility of muscle tissue. S100A1 is differentially expressed in epithelial ovarian cancer subtypes and its expression in endometrioid ovarian cancers is an indicator of poor prognosis. Defining a subset of endometrioid ovarian cancers with a poor prognosis has useful implications for patient management and treatment. S100A1 positive patients may benefit from more aggressive chemotherapy and more frequent checkups following initial debulking surgery. Nectin 4 is also overexpressed in ovarian cancer and there is differential expression among the subtypes. A soluble form of nectin 4 is detectable in patient sera. Compared to CA125, nectin 4 is more specific but less sensitive. When combined with CA125 for the detection of ovarian cancer, both the specificity and positive predictive value (PPV) were increased. Nectin 4 expression increases proliferation in ovarian cancer cells but does not alter survival to either cisplatin or taxol. Both nectin 4 expressing and control cells are able to form spheroids equally well. Together, these results demonstrate that biomarkers can improve diagnosis and detection of ovarian cancer. Future studies may clarify how S100A1 and nectin 4 influence ovarian cancer progression. Both proteins are potential targets for therapy. Targeting S100A1 in endometrioid ovarian cancer may increase survival. Nectin 4 expression in normal tissues is restricted to the placenta. This makes it an ideal target to utilize in therapy as there should be little killing of noncancerous tissues.