SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R C E L L B I O L O G Y P R O G R A M 2003 Kizu, R, Okamura, K, Toriba, A, Kakishima, H, Mizokami, A, Burnstein, KL , and Hayakawa, K. A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells. Archives of Toxicology 77:335-43, 2003. Yang, E and Burnstein, KL . Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. Journal of Biological Chemistry 278:46862-68, 2003. Chen, TC, Holick, MF, Lokeshwar, BL, Burnstein, KL , and Schwartz, GG. Evaluation of vitamin D analogs as therapeutic agents for prostate cancer. Recent Results in Cancer Research 164:273-88, 2003. Kizu, R, Okamura, K, Toriba, A, Mizokami, A, Burnstein, KL , Klinge, CM, and Hayakawa, K. Antiandrogenic activities of diesel exhaust particle extracts in PC3/AR human prostate carcinoma cells. Toxicology Sciences 76:299-309, 2003. HIGHLIGHTS/DISCOVERIES • Vitamin D inhibits the cell cycle by promoting nuclear exclusion of cdk-2, which opens up new avenues for prostate cancer therapy. Further, regulation of cdk-2 localization represents a new regulatory paradigm in G1 to S phase progression. KERMIT L. CARRAWAY, PH.D. Professor of Cell Biology and Anatomy DESCRIPTION OF RESEARCH For much of the past decade, Dr. Carraway’s primary research effort has been to examine the role of cell surface glycoproteins in mammary cancer, focusing on a particular glycoprotein complex (sialomucin complex, MUC4, rat Muc4) that his laboratory discovered about 20 years ago. This complex has both mucin- and growth factor-containing subunits. This putative bi-functionality can potentially contribute to two of the major attributes of cancer cells, loss of adhesiveness, and autonomous growth. Consistent with both of those activities, MUC4 has been implicated in tumor metastasis. The anti-adhesive function of MUC4 allows it to block tumor cell killing by lymphokine-activated killer (LAK) cells, a mechanism that permits the MUC4-overexpressing tumor cells to escape immune surveillance. One of the two growth factor domains of the transmembrane subunit of MUC4 has been shown to act as an intramembrane ligand for the class I tyrosine kinase growth factor receptor ErbB2/HER2/Neu. Binding of MUC4 as a ligand to ErbB2 potentiates tyrosine phosphorylation of the receptor and its co-receptor ErbB3, when the latter is stimulated with its soluble ligand Neuregulin. Researchers in Dr. Carraway’s laboratory are currently investigating the effects of this receptor modulation on downstream signaling pathways and cellular functions. Recently, they have found that induction of MUC4 overexpression in a melanoma tumor cell model potentiates both primary tumor growth and metastasis when the tumors are injected into nude mice. The former is correlated with a reduction in apoptosis in the MUC4-overexpressing animals. One important question is whether the anti-apoptotic effects of MUC4 result from its growth factor domains or other features of its structure. Recent results have shown that MUC4 can regulate both the phosphorylation and location of ErbB2 in polarized UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 69
T U M O R C E L L B I O L O G Y P R O G R A M epithelial cells, providing two mechanisms by which it can regulate signaling. Since MUC4 has been implicated in breast cancer progression, it is of interest to know how it is regulated in the mammary gland. Investigations of primary mammary epithelial cells indicate a major role for post-transcriptional regulation. Interactions with the extracellular matrix regulate MUC4 expression at the translational level, while transforming growth factor-beta (TGF-β) regulates it at the post-translational level. Both of these types of regulation are lost in rat mammary tumor cells, and both are known to change during human breast cancer progression. These and other results suggest that MUC4 acts as a “tumor progressor” gene rather than a primary oncogene. Thus, MUC4 might serve as a future target for prognosis and therapies in breast cancer. SELECTED PUBLICATIONS 2002 Carraway, KL , Perez, A, Idris, N, Jepson, S, Arango, M, Komatsu, M, Haq, B, Price-Schiavi, SA, Zhang, J, and Carraway, CA. Muc4/ sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: to protect and to survive. Progress in Nucleic Acid Research in Molecular Biology 71:149-85, 2002. Swan, JS, Arango, ME, Carothers Carraway, CA, and Carraway, KL . An ErbB2-Muc4 complex in rat ocular surface epithelia. Current Eye Research 24:397-402, 2002. Jepson, S, Komatsu, M, Haq, B, Arango, ME, Huang, D, Carraway, CA, and Carraway, KL . Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27 (kip), but does not activate mitogen-activated kinase or protein kinase B/Akt pathways. Oncogene 21:7524-32, 2002. Komatsu, M, Arango, ME, and Carraway, KL . Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysis. Biochemical Journal 368:41-48, 2002. 2003 Ramsauer, VP, Carothers Carraway, CA, Salas, PJ, and Carraway, KL . Muc4/Sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized Epithelial cells. Journal of Biological Chemistry 278:30142- 47, 2003. Carraway, KL , Ramsauer, VP, Haq, B, and Carothers Carraway, CA. Cell signaling through membrane mucins. BioEssays 25:66-71, 2003. Fischer, BM, Cuellar, JG, Diehl, ML, deFreytas, AM, Zhang, J, Carraway, KL , and Voynow, JA. Neutrophil elastase increases MUC4 expression in normal human bronchial epithelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 284:L671-79, 2003. Hu, YP, Haq, B, Carraway, KL , Savaraj, N, and Lampidis, TJ. Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells. Biochemical Pharmacology 65:1419-25, 2003. Soto, P, Price-Schiavi, SA, and Carraway, KL . SMAD2 and SMAD7 involvement in the posttranslational regulation of Muc4 via the transforming growth factor-beta and interferon-gamma pathways in rat mammary epithelial cells. Journal of Biological Chemistry 278:20338-44, 2003. Perez, A, Barco, R, Fernandez, I, Price-Schiavi, SA, and Carraway, KL . PEA3 transactivates the Muc4/sialomucin complex promoter in mammary epithelial and tumor cells. Journal of Biological Chemistry 278(38):36942-52, 2003. HIGHLIGHTS/DISCOVERIES • MUC4 expression potentiates the phosphorylation/activation of the ErbB2 and ErbB3 tyrosine kinase receptors induced by neuregulin, providing a mechanism by which MUC4 may contribute to tumor progression through changes in cell signaling pathways. 70 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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