Ovarian Cancer Signaling

Ovarian cancer is the most lethal gynecological cancer today, a predominant reason for this being an absence of early detection tests. Ovarian epithelial carcinoma is the most common of the ovarian malignancies. It is classified into histological subtypes: serous, endometrioid, clear cell and mucinous. Diverse signaling pathways are triggered depending on the cancer subtype.The two pathway model has been developed to explain ovarian cancer development and progression. According to this model, tumors can follow one of two pathways: Type I tumors that include low-grade serous, mucinous, endometrioid and clear cell carcinomas. They evolve gradually from benign cystadenomas and borderline lesions to malignant tumors; Type II tumors which include high-grade serous, high-grade endometrioid and undifferentiated carcinomas. These tumors develop rapidly and almost always involve the peritoneum.Mutations that play a significant role in pathogenesis of ovarian cancer include BRCA1, BRCA2, MLH1 and MSH2 (hereditary ovarian cancer) and K-Ras, B-Raf, PIK3CA, CTNNB1, PTEN and p53 (sporadic ovarian cancer). BRCA1, BRCA2, MLH1 and MSH2 are key molecules in various DNA repair pathways. Hence mutations in these genes leads to genomic instability and tumorigenesis. BRCA1 is also involved in a number of other biological processes like transcriptional regulation and ubiquitination. Mutations in BRCA1 and BRCA2 are associated with 90% of hereditary ovarian cancers. Activating mutations in K-Ras and B-Raf lead to activation of the ERK/MAPK pathway with far-reaching consequences for cell survival and angiogenesis. K-Ras mutations are found in low grade serous carcinomas. Mutations in the PIK3CA or PTEN genes leading to elevated expression the PI3K/PTEN/Akt/mTOR pathway can result in malignant transformation and uncontrolled cell growth. Another important mutation is in the CTNNB1 gene that is involved in Wnt signaling. This mutation is often found in endometrioid ovarian cancers, leading to increased cell adhesion, migration, invasion and metastasis. An understanding of the underlying genetic and molecular disorders in the different types of ovarian cancer will help in early detection and treatment of the disease.