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Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-B Inactivation

¹ Molecular Oncology Branch, Division of Basic Sciences, Research Institute and ² Cancer Biostatistics Branch, Center for Clinical Trials, National Cancer Center, Goyang, Kyonggi-do, Republic of Korea

Requests for reprints: Soo-Youl Kim, Molecular Oncology Branch, Division of Basic Sciences, National Cancer Center, Research Institute, 809 Madu-dong, Ilsandong-gu, Goyang, Kyonggi-do 410-351, Republic of Korea. Phone: 82-31-920-2043; Fax: 82-31-920-2006; E-mail: kimsooyoul{at}gmail.com.

Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-B (NF-B) activity. Increasing the level of TGase 2 in drug-sensitive cells by transient transfection reduced the level of inhibitory subunit of NF-B (IB) and increased NF-B activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IB, and this correlated with a shift in the accumulation of NF-B from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-B through polymerization and depletion of free IB during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-B may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)

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