Abstract
Paclitaxel is a first line chemotherapeutic agent for the patients with metastatic breast cancer. But inherited or acquired resistance to paclitaxel leads to poor response rates in a majority of these patients. To identify mechanisms of paclitaxel resistance, we developed paclitaxel resistant breast cancer cell lines, MCF-7 and 4T1 by continuous exposure to paclitaxel for several months. Western blot analysis showed increased expression of HER2 and β-catenin pathway in resistant cell lines as compared to parent cells. Hence, we hypothesized that HER2/β-catenin mediates paclitaxel resistance in breast cancer and suppression of HER2/β-catenin signaling could overcome paclitaxel resistance. Our data showed that penfluridol (PFL) treatment significantly reduced the survival of paclitaxel-resistant cells. Western blot analysis revealed that PFL treatment suppressed HER2, as well as, β-catenin pathway. In vivo data confirmed that PFL significantly potentiated tumor growth suppressive effects of paclitaxel in an orthotropic breast cancer model. In addition, tumors from paclitaxel and PFL-treated mice showed reduced HER2 and β-catenin expression, along with increased apoptosis. Taken together our results demonstrate a novel role of HER2/β-catenin in paclitaxel resistance and open up new avenues for application of PFL as a therapeutic option for overcoming paclitaxel resistance.
Highlights
Breast cancer remains the second leading cause of cancer related mortality in women, despite the advances in treatment strategies
The MCF-7, and MCF-7PR were treated with increasing concentrations of paclitaxel and their viability was evaluated via Sulforhodamine B (SRB) assay
There are few mechanisms which have been reported to be involved in paclitaxel resistance; such as activation of PI3K/Akt, hedgehog/GSK3β, drug transporters and β tubulin mutation[9,44,45,46]
Summary
Breast cancer remains the second leading cause of cancer related mortality in women, despite the advances in treatment strategies. Taxanes, including paclitaxel are approved and clinically used chemotherapeutic agents for the treatment of early and advanced metastatic breast cancer[4,5,6]. Several clinical studies have suggested the role of HER2 amplification in inducing chemotherapeutic resistance[16,17,18]. A clinical study has shown correlation between HER2 and β-catenin leading to poor prognosis in breast cancer patients[22,23]. Β-catenin plays role in cell response to paclitaxel treatment and in tamoxifen resistance in breast cancer[24,25]. Wnt/β-catenin signaling has been associated with the development and differentiation of cancer stem cells[31,32] To this end, no study has clearly demonstrated the involvement of Wnt/β-catenin signaling towards taxane resistance in breast cancer
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