$680,000 Award to Study How Estrogen Reacts With DNA

NYUCD has received a four-year, $680,000 grant to study how the metabolites of hormone estrogens react with DNA to create mutations leading to breast cancer. The NYUCD study is part of a larger breast cancer prevention and treatment study involving several other institutions cooperating in a Center Grant consortium under the auspices of the U.S. Department of Defense. This research could pave the way for the development of new approaches to breast cancer prevention, according to Dr. Joseph B. Guttenplan, Professor of Basic Science and Craniofacial Biology, and principal investigator on one subproject of the grant which will study mutations in mice and rats. Dr. Guttenplan’s laboratory is one of only a handful in the U.S. that can analyze and measure mutations in rat and mouse organs. Dr. Guttenplan is using the same mutation analysis model in oral cancer research studies.

“Estrogen increases the cell division rate, including the rate at which breast cells reproduce. However, if estrogens also cause mutations, the chance that the cellular reproduction leads to cancer would be greatly increased,” Dr. Guttenplan said. “My research, which is being conducted in cooperation with investigators at the University of Nebraska Medical School, examines the process by which estrogen damages DNA and triggers breast cancer in mice and rats.

“I will also look at the role that two substances may play in inhibiting estrogen-induced mutations. One of these substances — 1, 2-dithiole -3-thione — is found in cruciferous vegetables, such as cauliflower and broccoli. The other substance, N-acetycysteine, has been used in Europe for many years to treat cold symptoms and has chemical properties that indicate that it may play a role in cancer prevention. Results of these analyses could be used to incorporate the substances into the development of a drug or dietary supplement for breast cancer prevention.”

In another arm of the study, researchers will examine questions left unanswered by recent trials that found that new drug regimens can markedly reduce the chance that breast cancer will recur in postmenopausal women whose cancer was fueled by estrogen. Those women had stopped taking the drug tamoxifen, which blocks estrogen, because tamoxifen’s effectiveness diminishes after five years, or took another class of drugs (aromatase inhibitors) instead. The study found that members of this latter class of drugs, such as letrozole, can cut the yearly risk of cancer recurrence in half. In one case, the results were so strongly, and surprisingly, positive that the investigators ended the study early and offered the drug to women taking a placebo. However, questions remain, including how long women should take letrozole and at what doses. In addition, the important details in the mechanism by which drugs such as letrozole act have not been established. If these details are known, it may be possible to design even more effective treatments and/or better use for the current drugs.

The results of research conducted by Dr. Guttenplan and his colleagues will be combined with the letrozole study results and with findings from another trial on the prevention of mutations in cultured human breast cells. It is hoped that the combined results will ultimately be used to design and prepare a breast cancer prevention trial in women.