6.3.15 This year, MOCA provided a record $662,320 to 7 Minnesota ovarian cancer researchers, directed towards projects on ovarian cancer prevention or treatment. We’ve asked each MOCA-funded researcher to author a blog post detailing their projects. The first in this series is from Carol A. Lange, Ph.D., from the University of Minnesota.
MOCA provided Lange with a $100,000 grant for her project titled: BRCA Deficiency Drives an Enriched Sex Steroid Milieu that Supports Hereditary Ovarian Carcinogenesis.
Angelina Jolie’s poignant discussion about her inherited ovarian cancer risk and her prophylactic removal of ovaries and fallopian tubes has cast a spotlight on women impacted by a condition known as Hereditary Breast and Ovarian Cancer Syndrome (HBOC).
These women carry a mutation in the BRCA1 or BRCA2 genes that makes it more difficult for them to correctly repair damage to DNA – damage that can go on to cause more mutations and promote cancer initiation and progression. These mutations are present in all cells, but BRCA carriers tend to have the greatest cancer risk in tissues, like the fallopian tube, ovary and breast, that are very sensitive to the effects of the ovarian sex steroids, estrogen and progesterone.
Through their receptors – estrogen receptor (ER) and progesterone receptor (PR) – these steroids work to control cell growth and survival, while the BRCA proteins keep the effects of these steroids in check.
Recent studies reported that during a woman’s monthly cycle, BRCA carriers have higher levels of these steroids in their blood. In the context of BRCA deficiency, the lifetime exposure to elevated sex steroids without the ‘brakes’ of functional BRCA proteins may help promote the progression of ovarian cancer in women suffering from HBOC.
In our proposed research, we will address the hypothesis that BRCA carriers have a dysfunction of ovarian steroid production that results in elevated circulating sex steroids, leading to abnormal steroid-receptor-driven regulation of cellular processes, which promote ovarian cancer.
First, the ovaries of normal and BRCA carriers will be analyzed to confirm that the enzymes, receptors, and accessory proteins important to the formation of steroids are abnormally expressed and may lead to elevated steroid production.
Second, using fallopian tube epithelial cell models (the origin site of high grade serous ovarian cancer in commonly observed in women with HBOC) experiments will test for hormone-induced changes in ER/PR-regulated genes in the context of BRCA deficiency and elevated hormone levels.
Finally, we will use ER+/PR+ ovarian cancer cells to define the molecular mechanisms of ER and PR cross-talk with BRCA, with a focus on the role of progesterone and PR.
By understanding the relationship between sex steroids and BRCA in serous ovarian cancer development and progression, our studies may ultimately lead to future translational research aimed at providing less invasive, alternative management of women suffering from this devastating cancer syndrome.
Would you like more information about this research project or others that MOCA funds? Contact the MOCA office at (612) 822-0500.