Posted September 27, 2013
Denise Connolly, Ph.D., Fox Chase Cancer Center
While the risk for ovarian cancer due to BRCA mutations has become clearer since their discovery in the 1990s, the reasons why BRCA1 and BRCA2 mutations lead to cancer still are being studied. Dr. Denise Connolly was awarded a New Investigator Award in Fiscal Year 2003 (FY03) by the Department of Defense (DoD) Ovarian Cancer Research Program (OCRP) to develop and characterize a mouse model with the BRCA1 gene silenced in the ovarian surface epithelial cells, with or without concomitant silenced or mutated p53, a gene that is often found to be mutated in ovarian and other cancers. While the mice with the combined inactivated genes did develop ovarian cancer 54% of the time, this was often a type consistent with leiomyosarcoma (very rare in humans) as opposed to epithelial cancer (most common form of ovarian cancer). These results indicated that other genes that interact with BRCA1 are likely involved in the development of ovarian cancer.
Dr. Connolly was then awarded an OCRP Concept Award in FY06 to evaluate the effect of loss of BRCA1 and/or p53 in the environment around the ovarian epithelial cells. She found that loss of BRCA1 led mouse ovarian surface epithelial cells to move around in culture dishes more than control cells, an ability that is correlated with tumor invasiveness. She then conditioned growth media through exposure to cultured stromal (connective) cells that also had mutated BRCA1; this conditioned media then contains any secreted factors from the types of cells that would provide support in an organism, and removes the potentially confounding factor of having the two types of cells touching. Epithelial cells with mutated BRCA1 exposed to the conditioned media were strongly impacted by the change in environmental factors; programmed cell death was reduced by nearly half when the surrounding chemical signals were added. Cells with both BRCA1 and p53 mutations also had a decline in cell death. Cellular resistance to the normal avenues of cell removal is one of the ways that tumors form. Understanding how tumors might be created by these mutations opens the path to improved treatment targeting.
Quinn BA, Brake T, Hua X, Baxter-Jones K, Litwin S, et al. (2009) Induction of Ovarian Leiomyosarcomas in Mice by Conditional Inactivation of Brca1 and p53. PLoS ONE 4(12): e8404. doi:10.1371/journal.pone.0008404
Public and Technical Abstracts: Modeling Human Epithelial Ovarian Cancer in Mice by Alternation of Expression of the BRCA1 and/or p53 Genes
Public and Technical Abstracts: A Model System to Investigate the Effect of BRCA1 and/or p53 Inactivation in the Ovarian Stroma on Growth and Transformation Potential of the Ovarian Epithelium