Professor, Pharmacology & Chemical Biology
University of Pittsburgh
Breast cancer incidence rates are rising globally. Elevated levels of estrogens have been recognized as an important determinant of the risk of breast cancer. Studies in experimental laboratory models demonstrate that estradiol (E2) and estrone (E1) are carcinogenic and studies in cultured human cells provide a mechanistic basis for this effect. Observational studies and clinical trials consistently support the contention that sustained exposure to endogenous estrogens is associated with the development of sporadic breast cancer. Two complementary pathways are likely required for estrogen carcinogenicity. One involves signaling through the estrogen receptor (ER) leading to altered gene expression and increased proliferation accompanied by spontaneous mutations. The other pathway involves the oxidative metabolism of E1 or E2 to catechol estrogens and then reactive quinone metabolites. These metabolites can then directly and/or indirectly cause DNA damage and mutations responsible for the initiation and progression to breast cancer
There is a great need for frugal, effective approaches towards prevention of breast cancer. Dr. Kensler’s earlier work in pre-clinical models has demonstrated the efficacy of sulforaphane, a phytochemical from cruciferous vegetables such as broccoli, to alter estrogen metabolism and to reduce the DNA damaging actions of its quinone metabolites. These estrogen quinones are carcinogenic in experimental models. Moreover, elevated levels of these DNA-damage biomarkers are associated with increased risk of breast cancer in women. In their BCRF-funded project, his team will use biospecimens collected from a recently completed randomized clinical trial with a sulforaphane-rich broccoli sprout beverage to assess its effects on excretion of the estrogen-DNA damage products. If reductions are detected, use of broccoli sprout beverages may be a safe, efficient and inexpensive means for risk reduction in many populations.
Thomas Kensler is a Professor in the Department of Pharmacology & Chemical Biology at the Medical School of the University of Pittsburgh. He obtained his doctorate at the Massachusetts Institute of Technology and trained as a postdoctoral fellow at the McArdle Laboratory for Cancer Research at the University of Wisconsin and at the National Cancer Institute. After 30 years on the faculty of the Bloomberg School of Public Health at Johns Hopkins University, he moved his primary appointment to the University of Pittsburgh in 2010.
The goal of Dr. Kensler’s laboratory is to elucidate the biochemical and molecular mechanisms involved in the induction of cancer by chemicals to serve as a basis for the prevention, interruption or reversal of these processes in humans. One of the major mechanisms of protection against environmental carcinogenesis is the induction of enzymes involved in their metabolism, particularly those which facilitate their detoxication and elimination. Laboratory studies indicate that induction of these cytoprotective enzymes is a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally-occurring and synthetic chemical agents. The Nrf2 signaling pathway is broadly activated by these classes of chemopreventive agents and leads to increased expression of genes that enhance carcinogen detoxication and diminish oxidative stress and inflammation. A practical goal of Dr. Kensler’s research has been to develop the tools to test the hypothesis that activation of Nrf2 signaling is a useful strategy for chemoprevention in humans. His team conducted a series of “proof-of-principle” randomized clinical trials in populations at high risk for exposures to air- and food-borne toxins and carcinogens with oltipraz, chlorophyllin and broccoli sprout beverages rich in the phytochemical sulforaphane. They are now developing and validating biomarkers to assess the efficacy of broccoli-based interventions to mitigate the DNA damaging actions of reactive estrogen metabolites in the context of breast cancer prevention.
Dr. Kensler has received numerous awards including the AACR-American Cancer Society Award for Excellence in Cancer Epidemiology and Prevention (2007), Society of Toxicology Translational Impact Award (2009) and the National Friendship Award, Beijing, People’s Republic of China (2011), which is the country’s highest award for foreign civilians. He has published over 350 research articles. He is a former chair of the NIH Chemo-Dietary Study Section and is on the editorial board of several journals.