Signaling Pathways Contributing to High-Grade Serous Ovarian Cancer and Metastasis from Fallopian Tube

The fallopian tube epithelium (FTE) gives rise to high grade serous ovarian cancer (HGSOC), the most lethal gynecological malignancy. A mutation in p53 is reported in 96% of HGSOC. A transgenic mouse model and a cellular model with p53 mutation was developed and determined that p53 mutation alone is not sufficient to form tumors, however it significantly induced the cell migration. In vitro and In vivo analyses revealed that in FTE, mutant p53 reduced CDH6 (cell adhesion protein), through direct binding on CDH6 promoter, but CDH6 is not expressed in the ovaries. The existence of a FTE specific mutant p53 marker, may add to the existing tools for finding the cell of origin of HGSOC and may improve personalized therapies that work better in tumors arising from the FTE. In order to identify key drivers of HGSOC tumorigenesis, a spontaneous model of FTE derived cancer (MOEhigh - murine oviductal epithelium high passage, equivalent to human FTE) was made that contained gene alterations concordant to HGSOC. A human prolactin (PRL) like gene, Prl2c2 was amplified >100 fold in the model. Prl2c2 stable knockdown in MOEhigh cells demonstrated a significant reduction in cell proliferation, 2-dimensional foci, anchorage independent growth, and completely blocked tumor formation. The overall survival of ovarian cancer patients from transcriptome analysis of 1868 samples was lower when abundant PRL and prolactin receptors (PRL-R) were expressed. A HGSOC cell line (OVCAR3) and a tumorigenic human FTE cell line (FT33-Tag-Myc) were treated with recombinant PRL and a significant increase in cellular proliferation was detected. A CRISPR/Cas9 mediated PRL-R deletion in OVCAR3 and FT33-Tag-Myc cells demonstrated significant reduction in cell proliferation and eliminated tumor growth using the OVCAR3 model. PRL phosphorylated STAT5, m-TOR and ERK in ovarian cancer cells. Until now, PRL serum levels were only identified as a diagnostic marker for screening OVCA. However, this study for the first time, report that PRL is expressed and mediates tumorigenesis in human FTE. Small molecules were identified to block PRL-R activity and thereby providing a novel strategy, which with further clinical validation can be used to prevent HGSOC tumor formation from fallopian tube.