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 HIGHLIGHTS/DISCOVERIES • Observed the attachment of centrosomes to IF. Although the implications of the mechanism of detachment during mitosis are still to be assessed, this may be relevant for cancer therapy. OLUWATOYIN SHONUKAN, M.D. Assistant Professor of Medicine DESCRIPTION OF RESEARCH Malignant melanoma arises from the melanocytes, cells that originate in the neural crest. Normal melanocyte development in the neural crest and subsequent migration of the melanocyte precursors into the skin require trophic signals from the neurotrophin family of growth factors. With terminal differentiation, melanocytes lose expression of neurotrophin receptors. Following transformation, however, melanoma cells aberrantly express the receptors for the neurotrophins, with more advanced stages of the disease being more likely to express the neurotrophin receptors than the earlier stages. Dr. Shonukan’s research discovered that the melanoma cells also express several members of the neurotrophin growth factor family, thus suggesting that the neurotrophin/neurotrophin receptor system may be involved in the mediation of melanoma progression. The focus of her laboratory’s research is to understand the role of the neurotrophins and their receptors in the mediation of tumor progression in malignant melanoma. SELECTED PUBLICATIONS 2003 Shonukan, O, Bagayogo, I, McCrea, P, Chao, M, and Hempstead, B. Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin. Oncogene 22:3616-23, 2003. HIGHLIGHTS/DISCOVERIES • Nerve growth factor (NGF), the prototypic member of this family of growth factors, mediates the invasiveness of melanoma cells in vitro by inducing the coupling of the intracellular domain of the p75 neurotrophin receptor with the actin cytoskeleton. • Neurotrophin-induced melanoma invasiveness is mediated by signals generated through PI-3 kinase. • NGF induces the disruption of cadherin-mediated cell-cell adhesion, thereby permitting melanoma cells to dissociate from the keratinocytes in the epidermis and invade the dermis, from whence they metastasize to distant sites. Dr. Shonukan’s ongoing research efforts include identifying the components of this pathway in order to identify therapeutic targets. RAKESH SINGAL, M.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH Dr. Singal’s research focuses on the mechanisms that inactivate certain tumor-suppressor genes in prostate cancer. A common mode of such inactivation involves a modification (methylation) in DNA. By understanding how genes are silenced, treatments can be developed to activate them and thereby prevent the development and/ or progression of prostate cancer. Researchers in Dr. Singal’s laboratory also are studying methylation of selected genes as a diagnostic and prognostic marker in prostate cancer. The present screening techniques for prostate cancer are very inefficient, and two out of three patients undergo prostate biopsy unnecessarily to detect cancer. Cancer patients often have a small amount of DNA circulating in their serum, thought to be released from the cancer cells. Dr. Singal’s laboratory has shown that certain methylated genes are present at a substantially higher percentage in prostate cancer tissue but not in benign prostatic conditions. Researchers are UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 93
T U M O R C E L L B I O L O G Y P R O G R A M investigating if these methylated genes can be detected in serum DNA in patients with prostate cancer. If so, this test can be used as a part of prostate cancer screening, saving unnecessary prostate biopsies. DNA methylation plays a role during development by regulating gene expression. Another project in Dr. Singal’s laboratory focuses on understanding the role of methylation in regulating the expression of genes responsible for hemoglobin synthesis. Understanding the contribution of methylation to globin gene expression and the mechanisms involved will lead to the development of safe and effective therapies for globin gene disorders like thalassemia and sickle cell anemia. SELECTED PUBLICATIONS 2002 Singal, R, vanWert, JM, and Ferdinand, L Jr. Methylation of alpha-type embryonic globin gene alpha pi represses transcription in primary erythroid cells. Blood 100:4217-22, 2002. Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and Ginder, GD. Methylation of promoter proximal transcribed sequences of an embryonic globin gene inhibits transcription in primary erythroid cells and promotes formation of a cell type-specific methyl cytosine binding complex. Journal of Biological Chemistry 277:1897-1905, 2002. Noss, KR, Singal, R, and Grimes, SR. Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell lines. Anticancer Research 22:1505-11, 2002. 2003 Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal, R, and Gill, S. Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell carcinoma of lung. Endocrine Practice 9:233-35, 2003. JOYCE M. SLINGERLAND, M.D., PH.D., F.P.R.C. (C) Professor of Medicine DESCRIPTION OF RESEARCH Dr. Slingerland’s research investigates how cancers escape negative growth controls. Following her discovery of a key inhibitor of cell cycle progression, p27, Dr. Slingerland and her colleagues went on to demonstrate that p27 levels are reduced in up to 60 percent of common human cancers (breast, prostate, lung, ovarian, and others), in association with poor patient prognosis. Dr. Slingerland showed that the therapeutic effect of antiestrogens in breast cancer requires the cyclin-dependent kinase (cdk) inhibitors p21 and p27 to mediate growth arrest. Oncogenic activation of mitogenic signaling via the mitogenactivated protein kinase (MAPK) pathway deregulates p27 function, causing tamoxifen resistance in breast cancer. She provided key insights demonstrating the role of cell cycle inhibitors p15 and p27 as mediators of G1 arrest by transforming growth factor-beta (TGF-β) and demonstrated that cancer cells lose responsiveness to this growth inhibitory cytokine through loss or deregulation of p27. In a recent publication, her laboratory demonstrated that checkpoint loss during cancer progression makes p27 an essential mediator of arrest. They also showed that functional inactivation of p27 in human cancers can either occur through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. The laboratory recently showed that activation of mitogenic signaling via the receptor tyrosine kinases and the phosphoinositol 3’ kinase pathway alters p27 phosphorylation and function and the protein accumulates in the cytoplasm away from its targets in the nucleus. This work links oncogene activation with loss or inactivation of the cell cycle inhibitor, p27, elucidating a major mechanism of loss of growth control in cancer progression. Dr. Slingerland’s laboratory also is investigating the cause of aggressive estrogen receptor 94 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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