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(American Journal of Pathology. 2003;163:1781-1790.)
© 2003 American Society for Investigative Pathology

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

Janardhan Sampath^*, Pandy R. Long, Robert L. Shepard^*, Xiaoling Xia^*, Viswanath Devanarayan, George E. Sandusky, William L. Perry, III^*, Anne H. Dantzig^*, Mark Williamson, Mark Rolfe and Robert E. Moore^*

From the Cancer Research Division,^*the Molecular Pathology Division of Bio-Research Technologies and Proteins,and the Global Discovery and Development Statistics,Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; and Millennium Pharmaceuticals,Boston, Massachusetts

Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance.

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