| Summary: | 博士 === 臺灣大學 === 毒理學研究所 === 98 === Breast cancer is a major health threat world wide. It is the top cancer in women both in the developed and the developing world, comprising 16% of all female cancers. Optimal systemic treatment (adjuvant therapy) after breast cancer surgery is a crucial factor in reducing mortality in women with breast cancer, however a significant number of them still develop metastatic diseases and respond only transiently to conventional treatments leading to eventual mortality. So understanding the mechanism of drug resistance would help us to manage these patients and improved
their prognosis. Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes breast cancer metastasis. In the present study, we examined whether CTGF expression could confer drug resistance in human breast cancer. In breast cancer patients who received neoadjuvant chemotherapy, CTGF expression inversely correlated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability and resistance to apoptosis upon exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) decreased these effects. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cIAP1. Furthermore, CTGF overexpression resulted in activation of the ERK1/2 pathway. Inhibition of ERK1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. We also found that a C-terminal domain peptide from CTGF could exert similar activities to full-length CTGF in activation of ERK1/2, up-regulation of Bcl-xL/cIAP1 and resistance to apoptosis. We conclude that CTGF expression could confer resistance to chemotherapeutic agents through ERK1/2-mediated Bcl-xL/cIAP1 up-regulation of a survival pathway.
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