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Cell Cycle, Cell Death and Senescence

Down-Regulation of Thiamine Transporter THTR2 Gene Expression in Breast Cancer and Its Association With Resistance to Apoptosis¹

Departments of ¹ Pediatrics, ² Biochemistry, and ³ Chemistry, University of Kentucky, Lexington, KY

Requests for reprints: Jeffrey A. Moscow, Room J457, Department of Pediatrics, University of Kentucky, 740 S. Limestone, Lexington, KY 40536. Phone: (859) 323-1436; Fax: (859) 257-6048. E-mail: jmoscow{at}uky.edu

The recent molecular identification of two thiamine transporters, SLC19A2 (THTR1) and SLC19A3 (THTR2), has provided the opportunity to study thiamine transporter gene expression in human malignancies. We compared RNA levels of both THTR1 and THTR2 in a panel of human breast tumors and corresponding normal tissues. THTR2 RNA levels were down-regulated in breast cancer to 14% of the level found in corresponding normal tissues, while THTR1 levels were unchanged. Both thiamine transport genes were cloned and expressed in a breast cancer cell line to examine the impact of reconstituted thiamine transport gene expression on drug and radiation sensitivity and on resistance to apoptosis. THTR2-transfected breast cancer cells showed a 2.5-fold increase in specific THTR2 activity and a 3-fold increase in cytotoxicity against a bromoacetyl ester derivative of thiamine. Surprisingly, these cells also showed a 3-fold increase in sensitivity to doxorubicin and an increase in sensitivity to ionizing radiation, but no change in sensitivity to methotrexate or paclitaxel. TUNEL assays demonstrate an increase in apoptosis in THTR2-transfected cells exposed to doxorubicin and radiation, and Western blot analysis suggests that apoptosis associated with these cytotoxic stresses is mediated at least in part by a caspase-3-dependent pathway. Therefore, thiamine transporter THTR2 gene expression is down-regulated in breast cancer, which may contribute to resistance to apoptosis in these tumors.

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