Differential Impact of the Ubiquitin-Proteasome System on Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer

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Ovariancancer is particularly deadly and difficult to target because of its aggressive nature. With high mortality rates, current studies are focused on improving early detection and prevention methods as well as developing new treatments. To successfully develop these therapeutic options, researchers first need to understand how the cancer forms, spreads, and functions. Since ovarian cancer is composed of many heterogeneous subtypes, such as high-grade serous ovarian cancer and clear cell epithelial ovarian cancer, the nuances of each type need also be examined and understood in order to target each individually. It has been determined that each subtype has a unique relationship with the tumor suppressor, p53. Understanding how each subtype interacts with p53 can lead to specialized treatment mechanisms that target these interactions. MDM2 and ADRM1, over expressed in clear cell carcinoma and high grade serous ovarian cancer respectfully, are key components of these interactions within ovarian cancer. MDM2 is a negative regulator of p53, while ADRM1 aids in protein degradation. The overexpression of each molecule acts specifically to aid ovarian cancer in survival. In this review, recent advances in studying ovarian cancer subtypes will be covered, as well as how these subtypes relate to the ubiquitin-proteasome system and the key tumor suppressor in human cells, p53.

DUBs: Deubiquitinating Enzymes; HGSC: High-Grade Serous Ovarian Cancer; CCC: Clear Cell Carcinoma; MDM2: Murine Double Minute 2; UPS: Ubiquitin-Proteasome System; ROCA: Risk Of Ovarian Cancer Algorithm; CIC: Cancer Initiating Cell; BRCA: Breast Cancer Gene; ADRM1: Adhesion Regulating Molecule 1; CA-125: Serum Cancer Antigen-125.

Ovariancancer, one of the deadliest and most aggressive gynecological malignancies, is the fifth most common cause of cancer death in women. As recently as 2017, the annual ovarian cancer mortality was approximately 65% of the incidence rate due to low predictive value in screening procedures for women without increased risk factors. As a result, only 15% of patients are diagnosed with localized disease and many patients are diagnosed in stage III or IV. The four main histological subtypes within epithelial ovarian cancer are serous, clear cell, endometrioid, and mucinous adenocarcinomas. Each subtype has its own unique abnormalities, making diagnosis and treatment of ovarian cancer difficult. While all women are susceptible to ovarian cancer, increased risk factors include familial history, nulliparity, lack of breast feeding, and infertility. About 20% of ovarian cancers are familial, linked mostly to Breast Cancer Alleles 1 and 2, (BRCA1 or BRCA2), though other gene mutations have been implicated as well.