Faculty

Curriculum Vitae

B.A.- Biology, Wesleyan Univ. 1981
Ph.D- Genetics, Univ. N. Carolina at Chapel Hill 1986
Postdoctoral: Lineberger Cancer Research Center (with Dr. John Cidlowski), Univ. N. Carolina at Chapel Hill 1990
Research Instructor: Dept. of Physiology, Univ. N. Carolina at Chapel Hill 1990-1991
Assistant Professor, Univ. Miami 1991-1997
Associate Professor, Univ. Miami 1997-2003
Professor, Univ. Miami 2003-present
Director of Graduate Studies, 2001 - present

Research Interests

Our research focuses on signaling mechanisms that govern prostate cancer cell cycle and steroid hormone responsiveness. Vitamin D is of particular interest stemming from epidemiological data showing a relationship between vitamin D deficiency and increased risk of prostate cancer mortality. We and others showed that vitamin D inhibits the growth of prostate cancer cell lines and primary cell cultures derived from human prostate tumors. We found that the mechanism underlying this growth arrest is a vitamin D-induced cellular accumulation in the initial phase of the cell cycle, G1. We demonstrated that vitamin D mediated antiproliferative effects are not dependent on androgen and the androgen receptor. This finding is of clinical relevance, as a requirement for androgen would severely limit use of vitamin D in advanced prostate cancer, which is customarily treated by androgen ablation. Furthermore, we showed that vitamin D increases the levels of specific and potent cell cycle inhibitors, p21 and p27, a finding that has potentially important therapeutic implications. More recently, we made the novel discovery that vitamin D mediates the nuclear exclusion of cyclin dependent kinase 2 thereby decreasing its activity and promoting p27 stability leading to cell cycle arrest. Current efforts are to understand vitamin D regulation of cyclin dependent kinase 2 nucleocytoplasmic trafficking.

A finding that emerged from our studies on vitamin D was that the most highly malignant prostate cancer cell lines expressed very low levels of cyclin dependent kinase inhibitors. Subsequent studies on human prostate cancer biopsies confirmed this observation. Because of these findings and the fact that the genes encoding these inhibitors are rarely mutated, we have been pursuing intracellular signaling alterations that might suppress levels of these inhibitory proteins and contribute to uncontrolled cell proliferation. We made the novel observation that Rac1, a Ras-related Rho GTPase (small G protein) exhibits high activity in the more malignant prostate cancer cells. Specific inhibition of Rac1 in these cells results in increased levels of the cyclin dependent kinase inhibitor p21 and decreased proliferation. These findings are unique in describing a role for Rac1 in the regulation of p21 and implicate the Rac1 signaling pathway as a therapeutic target. Recently we found that a protein, which activates Rac1, also enhances the transcriptional activity of the androgen receptor. This observation provides a tantalizing link between two critical signaling pathways in prostate cancer and suggests a plausible mechanism for increased androgen receptor activity during progression to androgen independence.

Recent Publications

Lyons LS, Rao S, Balkan W, Faysal J, Maiorino CA, Burnstein KL (2007) Ligand-independent activation of androgen receptors by rho GTPase signaling in prostate cancer. Mol Endocrinol. [Epub ahead of print]

Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006) International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev. 58(4):782-97.

Lyons, L and Burnstein KL (2006) Vav3, a rho GTPase guanine nucleotide exchange factor, increases during progression to androgen independence in prostate cancer cells and potentiates androgen receptor transcriptional activity. Molecular Endocrinology 20(5):1061-72.

Burnstein KL (2005) Regulation of androgen receptor levels: implications for prostate cancer progression and therapy. J Cell Biochem. 95(4):657-69.

Balkan W, Burnstein KL, Schiller PC, Perez-Stable C, D'Ippolito G, Howard GA, Roos BA (2005) Androgen-induced mineralization by MC3T3-E1 osteoblastic cells reveals a critical window of hormone responsiveness. Biochem Biophys Res Commun 328(3):783-789.

Knight-Krajewski S, Welsh CF, Liu YQ, Yang E, Faysal J and KL Burnstein (2004) Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21(CIP1) levels in androgen independent human prostate cancer cells. Oncogene 23(32):5513-22.

Burnstein KL, Luetje CW (2004) Hormone resistance: it's SMRT to fight repression. Endocrinology 145(4):1525-6.

Kizu R, Otsuki N, Kishida Y, Toriba A, Mizokami A, Burnstein KL,
Klinge CM, Hayakawai K (2004) A new luciferase reporter gene assay for the detection of androgenic and antiandrogenic effects based on a human prostate specific antigen promoter and PC3/AR human prostate cancer cells. Anal Sci. 20(1):55-9.

Okamura K, Kizu R, Toriba A, Murahashi T, Mizokami A, Burnstein KL,
Klinge CM, Hayakawa K (2004) Antiandrogenic activity of extracts of diesel exhaust particles emitted from diesel-engine truck under different engine loads and speeds. Toxicology 195(2-3):243-54.

Schwartz GG, Eads D, Rao A, Cramer SD, Willingham MC, Chen TC, Jamieson DP, Wang L, Burnstein KL, Holick MF, Koumenis C (2004) Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. Carcinogenesis 25(6):1015-26.

Kizu R, Okamura K, Toriba A, Mizokami A, Burnstein KL, Klinge CM,
Hayakawa K (2003) Antiandrogenic activities of diesel exhaust particle extracts in PC3/AR human prostate carcinoma cells. Toxicol Sci. 76(2):299-309.

Yang E and KL Burnstein (2003) Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm J. Biol. Chem. 278(47):46862-8.

Chen TC, Holick MF, Lokeshwar BL, Burnstein KL, Schwartz GG (2003) Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. Recent Results Cancer Res. 164:273-88.

Burnstein KL (2002) Antiproliferative effect of vitamin D in prostate epithelial cells. In Steroid Hormones and Cell Cycle Regulation, Kerry L. Burnstein, ed. Norwell, MA: Kluwer Academic Publishers.

Yang ES, Maiorino CA, Roos BA, Knight-Krajewski S, Burnstein KL (2002) Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. Mol Cell Endocrinol. 186:69-79.

Grad JM, Lyons LS, Robins DM, Burnstein KL (2001) The androgen receptor (AR) amino-terminus imposes androgen-specific regulation of AR gene expression via an exonic enhancer. Endocrinology 142:1107-1116.

Tekur S, Kin-Mang L, Long J, Burnstein K, Ho S-M (2001) Expression of RFG/ELE1a/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: Regulation by methylation and sex steroids. Molecular Carcinogenesis 30:1-13.

Qadan LR, Perez-Stable CM, Schwall RH, Burnstein KL, Ostenson RC, Howard GA, Roos BA (2000) Hepatocyte growth factor and vitamin D cooperatively inhibit androgen-unresponsive prostate cancer cell lines. Endocrinology 141:2567-73.

Shen R, Sumitomo M, Dai J, Harris A, Kaminetzky D, Gao M, Burnstein KL, Nanus DM (2000) Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Endocrinology 141:1699-704.

Chen TC, Schwartz GG, Burnstein KL, Lokeshwar BL, Holick MF (2000) The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. Clin Cancer Res. 6:901-8.

Gkonos PJ, Guo F, Burnstein KL (2000) Type 1 vasoactive intestinal peptide receptor expression in PC3/AR cells is evidence of prostate epithelial differentiation. Prostate 42:137-44.

Schwartz GG, Lokeshwar BL, Burnstein KL. Correspondence re: S. E. Blutt, T. C. Polek, L. V. Stewart, M. W. Kattan, and N. L. Weigel, A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice. Cancer Res. 2001, 60: 779-782; Cancer Res. 2000; 61:4294.

Grad JM, Dai JL, Wu S, Burnstein KL (1999) Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Mol Endocrinol. 13:1896-911.

Lokeshwar BL, Schwartz GG, Seltzer MG, Burnstein KL, Zhuang S-H, Block NL, Binderup L (1999) Inhibition of prostate cancer metastasis in vivo: a comparison of 1 alpha, 25 dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiology Biomarkers & Prevention 8:241-248.

Zhuang S-H. and K.L. Burnstein (1998) The antiproliferative effect of 1 alpha,25-dihydroxyvitamin D3 in the human prostate cancer cell line LNCaP involves reduction of cyclin dependent kinase 2 activity and persistent G1 accumulation. Endocrinology 139:1197-1207