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 ment of metastatic potential of the transformed cell. Alternatively, SMC/MUC4 may be an important mediator of differentiation by its cell cycle inhibitory functions. MUC4 expression has been associated with several human malignancies, including some where MUC4 expression correlates with poor prognosis and others where the opposite association is seen. Immunocytochemical analyses have shown that the oral cavity is one of the earliest sites of expression of SMC during development of the rat, and that the molecule is expressed throughout the upper aerodigestive tract and in the salivary glands of the adult animal. This study postulates that human MUC4 is similarly expressed in the epithelia of the human upper aerodigestive tract and salivary glands, and that the molecule participates in the normal processes of cellular protection, repair, and replacement of these vulnerable tissues. It is further postulated that alterations in MUC4 expression are relevant to the cell biology of neoplastic transformation and subsequent invasion and metastasis of these cancers. The hypotheses of this study are threefold: 1) MUC4 expression is altered in head and neck malignancies compared with normal epithelial expression; 2) cellular expression of MUC4 modulates as lesions progress from dysplastic noninvasive lesions to invasive lesions with regional and distant metastases; 3) characterization of MUC4 expression in neoplasia will correlate with tumor behavior such as invasion and metastasis, and clinical outcomes such as likelihood of recurrence and prognosis. Preliminary data from immunoblotting studies using fresh frozen operative tissue samples and immunohistochemical localization studies using paraffin embedded tissue blocks have identified MUC4 throughout the normal human upper aerodigestive tract mucosa, and in major and minor salivary glands. MUC4 is identified in squamous cell carcinomas (SCCA) of the upper aerodigestive tract, as well as in metastatic cervical lymph nodes. SMC/MUC4 also is identified in a variety of salivary neoplasms. Alterations in the normal mucosal MUC4 expression are seen in otherwise histologically normal mucosa adjacent to invasive tumors. MUC4 expression in the salivary gland tumor mucoepidermoid carcinoma has been associated with improved prognosis independent of pathologic grade, the strongest known predictor of clinical behavior in this malignancy. No clear correlation between MUC4 expression and ErbB2 expression was seen by immunohistochemical analysis. On the other hand, MUC4 expression was noted to be expressed in the minority (14 percent) of head and neck SCCA, but a significant association between MUC4 expression and ErbB2 expression has been identified. Furthermore, MUC4 expression is associated with improved survival and decreased risk of recurrence in these tumors as established by immunohistochemical analysis. These studies suggest that in mucoepidermoid carcinoma and in head and neck SCCA MUC4 may be functioning as a marker or mediator of differentiation, with tumors that lose this expression associated with a more aggressive clinical course. These studies have established MUC4 as a novel molecular prognostic marker for these tumors. Mechanistic studies to better define the functional relationship between MUC4 and ErbB2 in these tumors are planned. SELECTED PUBLICATIONS 2003 Franzmann, EJ, Schroeder, GL, Goodwin, WJ, Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors. International Journal of Cancer 106:438-45, 2003. Civantos, FJ, Gomez, C, Duque, C, Pedroso, F, Goodwin, WJ, Weed, DT, Arnold, D, and Moffat, F. Sentinel node biopsy in oral cavity cancer: correlation with PET scan and immunohistochemistry. Head & Neck 25:1-9, 2003. Foster, PK and Weed, DT. Tongue viability after bilateral lingual artery ligation and surgery for recurrent tongue-base cancer. Ear, Nose, & Throat Journal 82:720-724, 2003. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 97
T U M O R C E L L B I O L O G Y P R O G R A M CATHERINE F. WELSH, M.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH Dr. Welsh studies the cell cycle progression through the G1 phase and its regulation by growth factor receptors and adhesion to the extracellular matrix. Her laboratory is particularly interested in how these signaling pathways contribute to breast cancer tumorigenesis and progression. Signals from the plasma membrane emanating from receptor tyrosine kinases as well as integrins are each required for G1 progression. Cell spreading and cytoskeletal integrity as a consequence of integrin engagement also are necessary. Their laboratory studies involve the role of Rho family GTPases, a subset of the Ras superfamily, in the regulation of adhesion-dependent cell cycle progression. These proteins have been shown to play a role in integrin- and growth factor-mediated signaling, and they are potent mediators of cytoskeletal architecture during cell spreading. They are therefore situated to play a key role in the regulation of adhesion-dependent cell cycle progression. Recent research has revealed that Rho GTPases become deregulated in breast cancer and may contribute to tumorigenesis. Dr. Welsh’s laboratory is currently investigating the contribution of Rho GTPases to abnormalities in cell cycle proteins that typify poor prognosis breast cancer. HIGHLIGHTS/DISCOVERIES • Rho family GTPases are in fact required for key adhesion-dependent G1 events, including cyclin D1 expression, Rb phosphorylation, and cyclin A expression. In addition, they participate in the activation of the mitogen-activated kinase, ERK1/2, a key upstream regulator of cyclin D1 expression. Furthermore, Rho proteins appear to be involved in determining the timing of cyclin D1 expression within G1 phase. • Hyperactivation of Rho proteins in a subset of breast cancers underlies abnormalities in cell cycle regulators that typify poor prognosis breast cancer. In addition, inactivation of Rho GTPases normalizes these regulatory molecules and restores a more orderly progression through the cell cycle, even in aggressively growing breast cancer cells. Pathways mediating these actions include the MEK-ERK pathway. These findings may have implications for more targeted therapeutic approaches that specifically inhibit the autonomous proliferation of breast cancer cells. RUDOLF K. WERNER, PH.D. Professor of Biochemistry and Molecular Biology DESCRIPTION OF RESEARCH Dr. Werner’s research focuses on the regulation of connexin43 expression. He and his colleagues had discovered that the 5’-UTR of connexin43 mRNA contains a very active internal ribosome entry site (IRES) element that appears to be regulated by estrogen. His laboratory continues to investigate this regulation in the myometrium where connexin43 is produced at parturition in response to estrogen. Dr. Werner’s research also has demonstrated that in several other tissues, such as heart and smooth muscle, connexin43 pre-mRNA is alternatively spliced producing mRNA with different 5’-UTRs but identical coding regions. This finding suggests that the expression of connexin43 is regulated at the translational level in different tissues. Dr. Werner and his colleagues discovered alternatively spliced 5’-UTR-coding exons in five other connexins. Again, the splicing seems to be tissue-specific. They currently are investigating whether some of these novel exons contain IRES elements. 98 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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G L O S S A R Y IFN—interferon IL
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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