Abstract
Improved prognosis for triple-negative breast cancer (TNBC) has plateaued and the development of novel therapeutic strategies is required. This study aimed to explore the anti-tumor effect of combined eribulin and HDAC inhibitor (vorinostat: VOR, pan-HDAC inhibitor and ricolinostat: RICO, selective HDAC6 inhibitor) treatment for TNBC. The effect of eribulin in combination with an HDAC inhibitor was tested in three TNBC cell lines (MDA-MB-231, Hs578T, and MDA-MB-157) and their eribulin-resistant derivatives. The expression of acetylated α-tubulin was analyzed by Western blotting for TNBC cells and immunohistochemical analyses for clinical specimens obtained from breast cancer patients who were treated with eribulin. The simultaneous administration of low concentrations (0.2μM) of VOR or RICO enhanced the anti-tumor effect of eribulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. Meanwhile, pretreatment with 5μM of VOR or RICO enhanced eribulin sensitivity in all three cell lines. Low concentration of VOR or RICO increased acetylated α-tubulin expression in MDA-MB-231 and Hs578T cells. In contrast, whereas 5μM of VOR or RICO increased the expression of acetylated α-tubulin in MDA-MB-157 cells, low concentrations did not. Eribulin increased the expression of acetylated α-tubulin in MDA-MB-231 and Hs578T cells but not in MDA-MB-157 cells. These phenomena were also observed in eribulin-resistant cells. Immunohistochemical analyses revealed that the expression of acetylated α-tubulin was increased after eribulin treatment in TNBC. HDAC6 inhibition enhances the anti-tumor effect of eribulin through the acetylation of α-tubulin. This combination therapy could represent a novel therapeutic strategy for TNBC.
Highlights
Improved prognosis for triple-negative breast cancer (TNBC) has currently plateaued and the development of novel therapeutic strategies is required
To evaluate potential growth-inhibitory effects by histone deacetylase (HDAC) inhibitors (VOR and RICO) on TNBC cells in vitro, MDA-MB-231, Hs578T, and MDA-MB-157 cells were treated with VOR or RICO for 72 h, and cell viability was measured by performing WST assays (Additional file 1; Table S1)
epithelial–mesenchymal transition (EMT) is not involved in enhanced eribulin sensitivity induced by HDAC inhibitors As we previously reported that EMT induction enhances eribulin sensitivity in a subset of TNBC cell lines (MDA-MB-231 and Hs578T) [14], we examined whether VOR or RICO treatment would alter EMT markers in these cell lines
Summary
Improved prognosis for triple-negative breast cancer (TNBC) has currently plateaued and the development of novel therapeutic strategies is required. Eribulin mesylate (eribulin) is an inhibitor of microtubule dynamics and has been used worldwide for the treatment of metastatic breast cancer since 2011. When administered to patients with metastatic breast cancer who had previously received both anthracycline and taxane, eribulin monotherapy significantly prolongs overall survival [9]. This drug is currently used for patients with recurrent or metastatic breast cancer
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