High grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer and it is now widely accepted that this disease often originates from the fallopian tube epithelium. PAX8 is a fallopian tube lineage marker with an essential role in embryonal female genital tract development. In the adult fallopian tube, PAX8 is expressed in the fallopian tube secretory epithelial cell (FTSEC) and its expression is maintained through the process of FTSEC transformation to HGSC. We now report that PAX8 has a pro-proliferative and anti-apoptotic role in HGSC. The tumor suppressor gene TP53 is mutated in close to 100% of HGSC; in the majority of cases, these are missense mutations that endow the mutant p53 protein with potential gain of function (GOF) oncogenic activities. We show that PAX8 positively regulates the expression of TP53 in HGSC and the pro-proliferative role of PAX8 is mediated by the GOF activity of mutant p53. Surprisingly, mutant p53 transcriptionally activates the expression of p21, which localizes to the cytoplasm of HGSC cells where it plays a non-canonical, pro-proliferative role. Together, our findings illustrate how TP53 mutations in HGSC subvert a normal regulatory pathway into a driver of tumor progression.

No abstract

Normal processes of embryonic development and abnormal transformation to cancer have many parallels, and in fact many aberrant cancer cell capabilities are embryonic traits restored in a distorted, unorganized way. Some of these capabilities are cell autonomous, such as proliferation and resisting apoptosis, while others involve a complex interplay with other cells that drives significant changes in neighboring cells. The correlation between embryonic development and cancer is driven by shared proteins. Some embryonic proteins disappear after embryogenesis in adult differentiated cells and are restored in cancer, while others are retained in adult cells, acquiring new functions upon transformation to cancer. Many embryonic factors embraced by cancer cells are transcription factors; some are master regulators that play a major role in determining cell fate. The paired box (PAX) domain family of developmental transcription factors includes nine members involved in differentiation of various organs. All paired box domain proteins are involved in different cancer types carrying pro-tumorigenic or anti-tumorigenic roles. This review focuses on PAX8, a master regulator of transcription in embryonic development of the thyroid, kidney, and male and female genital tracts. We detail the role of PAX8 in each of these organ systems, describe its role during development and in the adult if known, and highlight its pro-tumorigenic role in cancers that emerge from PAX8 expressing organs.