Abstract
This study aimed to elucidate the mechanisms underlying the resistance of breast cancer to eribulin. Seven eribulin-resistant breast cancer cell lines (MCF7/E, BT474/E, ZR75-1/E, SKBR3/E, MDA-MB-231/E, Hs578T/E, and MDA-MB-157/E) were established. mRNA and protein expression of ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 11 (ABCC11) increased in all eribulin-resistant cell lines compared to the parental cell lines. When ABCB1 or ABCC11 expression was inhibited by small interfering RNA in MCF7/E, BT474/E, and MDA-MB-231/E cells, eribulin sensitivity was partially restored. Moreover, eribulin resistance was attenuated additively by inhibiting ABCB1 and ABCC11 in MCF7/E cells. Additionally, overexpression of exogenous ABCB1 or ABCC11 in HEK293T cells conferred resistance to eribulin. MCF7/E and MDA-MB-231/E cells showed cross-resistance to paclitaxel, doxorubicin, and fluorouracil. Inhibition of ABCB1 partially restored paclitaxel and doxorubicin sensitivity. Partial restoration of fluorouracil sensitivity was induced by inhibiting ABCC11 in MCF7/E and MDA-MB-231/E cells. Both ABCB1 and ABCC11 are involved in the development of eribulin resistance in breast cancer cells in vitro regardless of the breast cancer subtype. Thus, ABCB1 and ABCC11 expression may be used as a biomarker for predicting the response to eribulin in patients with breast cancer. Concomitant inhibition of ABCB1 and ABCC11 might help enhance the antitumor effects of eribulin.
Highlights
Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and is an inhibitor of microtubule dynamics [1, 2]
Both ATP-binding cassette subfamily B member 1 (ABCB1) and ABCC11 are involved in the development of eribulin resistance in breast cancer cells in vitro regardless of the breast cancer subtype
Expression of ABCB1 was not inhibited by transfection with the ABCC11-targeting small interfering RNA (siRNA), and expression of ABCC11 was not inhibited by transfection with the ABCB1-targeting siRNA (Figure 3E). Inhibition of both ABCB1 and ABCC11 expression in the MCF7/E cells restored eribulin sensitivity to approximately the level observed for the parental MCF7 cells (Figure 3F). These results demonstrate that inhibiting the expression of either ABCB1 or ABCC11 restored the sensitivity to eribulin, the degree of restoration varied depending on the cell line, indicating that ABCB1 and ABCC11 are involved in the development of eribulin resistance in these breast cancer cells
Summary
Eribulin mesylate (eribulin) is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and is an inhibitor of microtubule dynamics [1, 2]. Most patients fail to respond to eribulin within several months, a phenomenon that has been observed for many other cytotoxic drugs that were previously administered for breast cancer, and the mechanisms underlying this resistance to eribulin have not been fully elucidated. ATP-binding cassette (ABC) transporters are primary active transporters that confer drug resistance by effluxing anticancer agents [4]. ABC transporters consist of 48 members that are classified into seven subfamilies from ABCA to ABCG based on their sequence similarity [5]. ABC subfamily B member 1 (ABCB1)/Pglycoprotein (MDR1) has been implicated as the major efflux transporter responsible for the resistance of cancer cells to many anticancer agents such as cisplatin, docetaxel, anthracyclines (doxorubicin, epirubicin), etoposide, irinotecan, methotrexate, paclitaxel, and vincristine [5, 6]. Among the ABCC subfamily members, ABCC1 (MRP1) and ABCC2 (MRP2)
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