Metastasis

Mesenchymal stem cell

Paclitaxel

Vimentin

Cancer research

Triple-negative breast cancer

Epithelial–mesenchymal transition

Metastatic breast cancer

Internal medicine

Pharmacology

Eribulin

Medicine

Immunohistochemistry

Breast cancer

Cancer

Pathology

Oncotarget

// Takaaki Oba 1 and Ken-Ichi Ito 1 1 Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery II, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan Correspondence to: Ken-Ichi Ito, email: kenito@shinshu-u.ac.jp Keywords: eribulin; paclitaxel; triple-negative breast cancer; epithelial-mesenchymal transition; mesenchymal-epithelial transition Received: December 26, 2017 Accepted: April 05, 2018 Published: May 01, 2018 ABSTRACT Improved prognosis for triple-negative breast cancer (TNBC) has currently plateaued and the development of novel therapeutic strategies is required. Therefore, we aimed to explore the anti-tumor effect of eribulin and paclitaxel combination therapy for TNBC. The effect of eribulin and paclitaxel in combination was tested, with both concurrent and sequential administration, using four TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-157, and Mx-1) in vitro and in an MDA-MB-231 BALB/c-nu/nu mouse xenograft model. The expression of epithelial-mesenchymal phenotypic markers was analyzed by western blotting and immunohistochemical analyses. Simultaneous administration of eribulin and paclitaxel resulted in a synergistic anti-tumor effect with MDA-MB-231 and Hs578T cells, but not MDA-MB-157 and Mx-1 cells, in vitro . Moreover, pre-treatment with one drug significantly enhanced sensitivity to the subsequently administrated second drug in MDA-MB-231 and Hs578T cells. Eribulin increased E-cadherin expression and decreased the expression of mesenchymal markers in MDA-MB-231 and Hs578T cells. In contrast, paclitaxel increased the expression of mesenchymal markers. When epithelial-mesenchymal transition was induced by TGF-β1, eribulin sensitivity was enhanced. In contrast, a TGF-β receptor kinase inhibitor decreased eribulin sensitivity. In MDA-MB-231 tumor-bearing mice, concurrent administration of low doses of eribulin and paclitaxel significantly inhibited tumor growth compared to that with either monotherapy. Moreover, single administration of eribulin before the initiation of paclitaxel treatment decreased vimentin expression and reduced the average tumor volume in a mouse xenograft model. Eribulin and paclitaxel show synergistic anti-tumor effect by altering the epithelial-mesenchymal phenotype. This combination therapy could represent a novel therapeutic strategy for TNBC.

Combination of two anti-tubulin agents, eribulin and paclitaxel, enhances anti-tumor effects on triple-negative breast cancer through mesenchymal-epithelial transition