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The involvement of Mullerian Inhibiting Substance in ovarian cancer

By Robin Arnette
October 2010

Harvard Professor Patricia K. Donahoe, M.D.
Donahoe is the Marshall K. Bartlett Professor of Surgery and Director of the Pediatric Surgical Research Laboratories at the Harvard Medical School Massachusetts General Hospital. (Photo courtesy of Steve McCaw)

Kenneth Korach, Ph.D.
Korach praised Donahoe's exemplary career by saying, "She took a clinical observation and made it a basic science question and found the gene, receptor, and the signaling pathway. That is how an investigator makes a major impact [on a field]." (Photo courtesy of Steve McCaw)

Mitch Eddy, Ph.D., and William Schrader, Ph.D.
Laboratory of Reproductive and Developmental Toxicology investigator Mitch Eddy, Ph.D., and Deputy Scientific Director William Schrader, Ph.D., listened intently to the lecture. (Photo courtesy of Steve McCaw)

Retha Newbold and Jack Bishop, Ph.D.
National Toxicology Program Staff Scientist Retha Newbold and Toxicology Branch Geneticist Jack Bishop, Ph.D., were part of the heavily attended seminar. (Photo courtesy of Steve McCaw)

According to Harvard Professor Patricia K. Donahoe, M.D., Mullerian Inhibiting Substance (MIS), a protein involved in human sex determination, can play an important role in the treatment of a progenitor-like subset of cells in human ovarian cancer. This research may lead to patient specific treatment strategies and could produce novel therapies for ovarian cancer, an illness with few treatment options.

Donahoe discussed the work during the first lecture of the 2010-2011 NIEHS Distinguished Lecture Series on September 14. As the first woman to receive a full professorship in the department of surgery at Harvard Medical School, Donahoe began her talk by explaining how she started studying cancer.

"MIS from the testes in a developing male embryo causes the Mullerian duct to completely regress," she said. "It occurred to us early in the course of these studies that if there was a substance that caused complete regression of a fetal duct, it would be interesting to find out whether it had an effect on tumors emanating from that same embryonic source." The Mullerian duct gives rise to the Fallopian tubes, uterus, cervix, and upper portion of the vagina in the female.

She went on to say that since she and others made that connection in the 1970s, scientists have determined that many of the pathways important in embryonic development are also expressed in human cancers. One of the first people to see a link was Bob Scully, M.D., a Massachusetts General Hospital cancer pathologist who found that ovarian cancer, clinically known as a serous cysadenocarcinoma, resembled the Fallopian tube.

Donahoe explained that MIS is a member of the TGFbeta family. When she and her group tested MIS — made in the laboratory by David MacLaughln, Ph.D. — against a number of mouse Mullerian duct tumors called MOVCARs and human ovarian cancer cell lines, they saw regression of the tumors. Donahoe originally worked with a pharmaceutical company to clone MIS and produce recombinant MIS; she is now attempting to establish a partnership with industry to produce sufficient MIS for clinical trials. This larger quantity of MIS will allow her team to shed more light on the molecular mechanisms by which MIS causes the inhibition of growth of ovarian cancers.

"We know that MIS downstream signaling occurs through the SMAD1, 5, and 8, and that subsequent release of FKBP12, affects multiple pathways that will determine how the drug works downstream."

Donahoe's goal is to be able to separate the cells from an ovarian tumor into two populations: stem cell enriched and non-stem cell. After completing that step, she'd like to test the responsiveness of both cell groups to chemotherapeutic agents and biologics such as MIS. "We can then determine expression profile differences and begin to understand the molecular basis for asymmetric cell division, which is one of the great unsolved biological mysteries," she added.

Kenneth Korach, Ph.D., Chief of the Laboratory of Reproductive & Developmental Toxicology, served as host for Donahoe's seminar.

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