Direct modulation of progesterone signaling appears to influence ovarian cancer risk

A woman's risk of ovarian cancer rises significantly if she carries either of two previously unexamined variations in the gene that codes for the progesterone receptor, according to a team of researchers led by scientists from the Keck School of Medicine of the University of Southern California.

The study, which is being published in the January 5th issue of the Journal of the National Cancer Institute, was initially supposed to be a more in-depth look at one particular version-or allele-of the progesterone receptor gene (PGR). The PROGINS allele, says Celeste Leigh Pearce, a preventive medicine researcher from the USC/Norris Comprehensive Cancer Center and the paper's first author, had previously been linked to a higher ovarian cancer risk as well as a lower breast cancer risk in women who carry it.

To see if the PROGINS allele did indeed confer a higher ovarian cancer risk on women, the researchers-led by the study's principal investigator, USC preventive medicine professor Malcolm Pike-first used biological samples collected by the Hawaii/Los Angeles Multiethnic Cohort Study. (The Multiethnic Cohort is one of the largest ongoing population studies in the world, and is led by Brian E. Henderson, M.D., the Kenneth T. Norris Jr. Chair in Cancer Prevention and dean of the Keck School of Medicine.) The scientists examined the variety of genetic variations found in the PGR gene as part of a long-term collaboration between USC researchers and those at the Broad Institute in Cambridge, MA, looking to ascertain if the PROGINS allele held a particular risk of ovarian cancer for women.

The results, Pearce notes, showed that it likely does. But at the same time, they noticed something even more interesting. The data they collected showed that the biggest influence on ovarian cancer risk from that region of the gene came not from the single PROGINS allele, but rather from two haplotypes found in the same region, one of which actually contains the PROGINS allele. (A haplotype is a set of alleles on a chromosome that are closely linked together, and which are usually passed down as a single unit.)

In fact, the two haplotypes-dubbed simply 4-D and 4-E-were found to raise ovarian cancer risk by almost 3.5-fold in women who carry two copies of either haplotype, or one of each. Not only were these two particular haplotypes found to be part of the story, but they were found to overshadow the role of the PROGINS allele.

How can subtle changes in a progesterone receptor gene lead to an elevated risk of this uncommon, yet exceedingly deadly, form of cancer in women remains to be fully spelled out.

What scientists do know, however, is that progesterone appears to protect women from the disease, while increasing their risk of breast cancer. And so it seems likely that subtle changes in the progesterone receptor, which is the first step in the signaling pathway by which the progesterone hormone does its job, might decrease the receptor's efficiency, muting progesterone's signal and reducing its influence on the body's cells. And that, in turn, might very well lead to ovarian cancer.

Of course, proving that theory will take time and further studies, notes Pearce. But, by that same token, it would likely provide invaluable information, and possibly new therapeutic options as well.

"If our findings with respect to ovarian cancer are replicated in other studies, this would provide important evidence that direct modulation of progesterone signaling influences cancer risk," the researchers note. "Understanding how this variation influences risk of ovarian cancer should give further insight into ways this difficult-to-diagnose disease could be prevented in the future."