Abstract
Connective tissue growth factor (CTGF) expression is elevated in advanced breast cancer and promotes metastasis. Chemotherapy response is only transient in most metastatic diseases. 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 was inversely associated with chemotherapy response. Overexpression of CTGF in MCF7 cells (MCF7/CTGF) enhanced clonogenic ability, cell viability, and resistance to apoptosis on exposure to doxorubicin and paclitaxel. Reducing the CTGF level in MDA-MB-231 (MDA231) cells by antisense CTGF cDNA (MDA231/AS cells) mitigated this drug resistance capacity. CTGF overexpression resulted in resistance to doxorubicin- and paclitaxel-induced apoptosis by up-regulation of Bcl-xL and cellular inhibitor of apoptosis protein 1 (cIAP1). Knockdown of Bcl-xL or cIAP1 with specific small interfering RNAs abolished the CTGF-mediated resistance to apoptosis induced by the chemotherapeutic agents in MCF7/CTGF cells. Inhibition of extracellular signal-regulated kinase (ERK)-1/2 effectively reversed the resistance to apoptosis as well as the up-regulation of Bcl-xL and cIAP1 in MCF7/CTGF cells. A neutralizing antibody against integrin alpha(v)beta(3) significantly attenuated CTGF-mediated ERK1/2 activation and up-regulation of Bcl-xL and cIAP1, indicating that the integrin alpha(v)beta(3)/ERK1/2 signaling pathway is essential for CTGF functions. The Bcl-xL level also correlated with the CTGF level in breast cancer patients. We also found that a COOH-terminal domain peptide from CTGF could exert activities similar 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 augmenting a survival pathway through ERK1/2-dependent Bcl-xL/cIAP1 up-regulation.
Highlights
Connective tissue growth factor (CTGF), known as CTGF/ CCN2, belongs to the CCN family [1], consisting of six members: CTGF, NOVH, CYR61, WISP-1, WISP-2, and WISP-3 [2], all of whichNote: Supplementary data for this article are available at Cancer Research Online.Despite the proven survival benefit of systemic adjuvant chemotherapy in breast cancer patients, a significant number of them still develop metastatic diseases and respond only transiently to conventional treatments leading to eventual mortality
Because highly metastatic cancer cells exhibit a drug-resistant phenotype [14], we speculated that CTGF expression might increase drug resistance in breast cancer cells
We show that CTGF overexpression in human breast cancer cells enhances chemoresistance through inhibition of apoptosis
Summary
Despite the proven survival benefit of systemic adjuvant chemotherapy in breast cancer patients, a significant number of them still develop metastatic diseases and respond only transiently to conventional treatments leading to eventual mortality. In Greenberg’s report, only 16.6% of metastatic breast cancer patients achieved complete response by cytotoxic chemotherapy [12]. Even with targeted therapy using trastuzumab against HER2/neu overexpressing breast cancer, complete response was
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