title: Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines.
abstract: Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC.
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Terashima
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Marco A
authors.initials: MA
authors.lastname: De Velasco
authors.affiliation: Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511 Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
keywords: 5-FU; EMT; Eribulin; MET; S-1; TNBC