Sylvester Comprehensive Cancer Center

Kerry L. Burnstein, Ph.D.

Kerry L. Burnstein, Ph.D.

Professor of Molecular & Cellular Pharmacology

Description of Research

Dr. Burnstein's research focuses on mechanisms that control cellular responses to steroid hormones particularly in endocrine cancers. A major interest is the regulation of androgen receptor action in prostate cancer and androgen receptor-mediated mechanisms in the development of therapeutic resistance. Androgen withdrawal is a mainstay therapy for advanced prostate cancer. While this therapy results in prostate cancer regression, eventually prostate cancer growth resumes in virtually all patients. The androgen receptor continues to drive cancer growth in recurrent disease despite decreased circulating androgen levels. Dr. Burnstein's lab demonstrated that levels of Vav3, a Rho GTPase guanine nucleotide exchange factor, increase during prostate cancer progression following androgen withdrawal therapy. Vav3 enhances androgen receptor transcriptional activity and prostate cancer growth. Vav3 is an activator of the small Rho GTPase, Rac1, and they showed further that Rac1 is sufficient for recurrent growth of prostate tumors under conditions of androgen deprivation. Similar to findings in prostate cancer, Vav3 is also up-regulated in breast cancer compared to normal breast tissue. Vav3 and Rac1 enhance estrogen receptor and androgen receptor activities, and inhibition of Rac1 effectively inhibits cancer growth. The Burnstein lab is currently examining the molecular basis for the tumorigenic activities of Vav3/Rac1 and evaluating Rac1 as a drug target in endocrine cancers.

Dr. Burnstein also has a long-standing interest in the cancer protective and antiproliferative actions of the hormonal form of vitamin D (1,25 dihydroxyvitamin D3), which are mediated by the vitamin D receptor, a member of the steroid receptor family. Her lab and others showed that vitamin D inhibits the growth of breast and prostate cancer cells by promoting cell cycle arrest in the G1 phase. Dr. Burnstein's group found that vitamin D promotes the nuclear exclusion of cyclin dependent kinase 2 thereby decreasing its activity and leading to cell cycle arrest. Her lab recently identified a novel vitamin D receptor target gene, GADD45&gamma that participates in vitamin D-mediated growth inhibition. Failure of vitamin D to induce GADD45&gamma is one mechanism for vitamin D resistance in prostate cancer cells.

While the necessity for vitamin D in maintaining bone health is well-known, additional benefits of this nutrient, most notably, cancer protection are emerging. Inadequate vitamin D status is a serious health concern particularly among the elderly, who are also at greatest risk for many cancers. In initial efforts to understand the molecular basis for the cancer protective effects of vitamin D, Dr. Burnstein and collaborators in the Department of Medicine and the Hussman Institute for Human Genomics, are examining global epigenetic changes in the genomes of elderly individuals following vitamin D supplementation. Their ultimate goal is to identify genes that are epigenetically regulated following long-term vitamin D exposure and are responsible for decreased cancer risk.

Highlights

  • Discovered that vitamin D promotes cell cycle arrest through relocalization of Cdk2 to the cytoplasm where it is inactive. Understanding the mechanism of vitamin D action will promote the effective and rationale use of this agent in cancer prevention and treatment.
  • Identified elevated Vav3/Rac1 signaling to the androgen receptor in advanced prostate cancer. Vav3 and Rac1 are novel and potentially valuable therapeutic targets.

Selected Cancer-Related Publications

  • Rosenblatt AE, Burnstein KL. Inhibition of androgen receptor transcriptional activity as a novel mechanism of action of arsenic. Mol Endocrinol 23:412-21, 2009. Read more »
  • Lee JG, Zheng R, McCafferty-Cepero JM, Burnstein KL, Nanus DM, Shen R. Endothelin-1 enhances the expression of the androgen receptor via activation of the c-myc pathway in prostate cancer cells. Mol Carcinog 48:141-9, 2009. Read more »

Programs

Collaborating in the Multidisciplinary Research Program(s):

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