Abstract
Abstract Background: Eribulin is a key drug for the patients with metastatic breast cancer; however, the mechanisms of how breast cancer cells become resistant to eribulin have not been fully elucidated. The purpose of this study is to analyze the mechanisms of eribulin resistance in breast cancer cells. Cell lines: Eribulin resistant cell lines were established for three estrogen receptor (ER) positive cell lines (MCF7/E, BT474/E,ZR75-1/E), three triple negative cell lines (MDA-MB-231/E, Hs578T/E, MDA-MB-157/E), and one HER2 positive cell line (SKBR3/E) by exposing to stepwise increased doses of eribulin. Results: The mRNA and protein expressions of both ABCC11 and ABCB1 were increased in all eribulin resistant cell lines regardless of their subtype. Inhibition of either ABCC11 or ABCB1 by small interfering RNA (siRNA) partially restored the sensitivity to eribulin in MCF7/E, BT474/E, and ZR75-1/E cells. Moreover, dual inhibition of ABCC11 and ABCB1 additively restored the sensitivity to eribulin in MCF7/E cells. On the other hand, overexpression of exogenous ABCC11 caused eribulin resistance in MCF7 and MDA-MB-231 cells (resistance ratio; MCF7; 13.8±0.85, MDA-MB-231; 11.4±0.74). Interestingly, inhibition of ER expression by siRNA or down regulation of ER by fluvestrant decreased ABCC11 expression and increased the sensitivity to eribulin in MCF7/E cells. Discussion: Our data demonstrates that ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells regardless of their subtype; moreover, our data suggests the possibility of involvement of ER pathway in the regulation of ABCC11 expression in the ER positive breast cancer cells. Although further studies should be required, the expression of ABCC11/ABCB1 may be used as biomarkers for prediction of response to eribulin in breast cancer. In addition, the inhibition of ABCC11/ ABCB1 might be of service in a novel strategy to enhance the antitumor effect of eribulin. Citation Format: Takaaki Oba, Ken-ichi Ito, Shun’ichiro Taniguchi. ABCC11/MRP8 and ABCB1/MDR1 confer eribulin resistance to breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2112.
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