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Role of Cyclin E as an Early Event in Ovarian Carcinogenesis

2012-04-01 16:04:07

DOTA; 2012 Apr; DOI: dtic.mil/cgi-bin/GetTRDoc?AD=ADA533483


Christine Walsh



Abstract



Cyclin E amplification and overexpression characterizes a subset of epithelial ovarian cancers. We hypothesized that this subset of tumors may demonstrate an enhanced response to targeted therapy with the proteasome inhibitor, bortezomib. Cyclin E also exists in multiple low molecular weight (LMW) isoforms in cancer cells which demonstrate greater neoplastic activity. A natural dietary phytochemical called Indole-3-Carbinol (I3C) disrupts cyclin E processing through the inhibition of the enzyme that cleaves cyclin E into its LMW isoforms. When combining I3C with bortezomib, we found I3C to synergistically sensitize ovarian cancer
cells to bortezomib. This finding has translational potential as bortezomib as a single-agent was found to have minimal activity in a phase II treatment trial of recurrent ovarian cancer. This finding could re-introduce bortezomib to the therapeutic armamentarium against ovarian cancer if the in vitro results replicate in
mice and humans.



Introduction



We are interested in defining the genetic changes that initiate and drive the aggressive behavior of epithelial ovarian malignancies. In a pilot study looking at the genetic changes occurring across the whole genome of high-grade papillary serous ovarian cancers, we identified cyclin E as an interesting candidate gene. We found high-copy number amplification of the cyclin E gene locus to be the single most notable recurrent genetic event. Furthermore, epidemiological evidence links the subset of cyclin E overexpressing epithelial ovarian cancers to an increased number of lifetime ovulatory cycles and the “incessant ovulation” theory of
ovarian cancer causality. Experimental systems have shown deregulation of cyclin E levels to result in chromosomal instability, a hallmark feature of epithelial ovarian cancers. This led us to hypothesize that cyclin E deregulation is an important initial event in ovarian carcinogenesis. We proposed three specific aims: (1) to characterize the genetic events induced along with cyclin E amplification and overexpression; (2) to determine the role of cyclin E and its collaborating genetic events in ovarian cancer initiation; and (3) to define the subset of ovarian cancers with impaired cyclin E in hibition and to determine whether these
tumors demonstrate an enhanced response to targeted therapy. Here, we report research accomplishments from the first year of the study.



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