Abstract
Multidrug resistance-associated protein 1 (MRP1) is an important efflux transporter and overexpression of MRP1 usually leads to chemoresistance in breast cancer. Here, we found MRP1 overexpressed in human breast cancer tissues and breast cancer cell lines (compared with normal breast tissues and cell line, respectively). And MRP1 level increased in doxorubicin resistant MCF-7 cells compared with parental MCF-7 cells. Increasing evidences suggest microRNAs (miRNAs) influence chemotherapy response. We found miR-145 level decreased in human breast cancer tissues, breast cancer cell lines and doxorubicin resistant MCF-7 cells, and inversely correlated with MRP1 expression level. In the process of constructing MCF-7 doxorubicin resistant cell line, escalating doxorubicin markedly decreased miR-145 level, following by increased MRP1 level. Further study showed, miR-145 suppressed MRP1 expression by directly targeting MRP1 3′-untranslated regions. Overexpression of miR-145 sensitized breast cancer cells to doxorubicin in vitro and enhanced to doxorubicin chemotherapy in vivo through inducing intracellular doxorubicin accumulation via inhibiting MRP1. Taken together, our study revealed miR-145 sensitizes breast cancer to doxorubicin by targeting MRP1 and indicated the potential application in developing MRP1 inhibitor.
Highlights
Breast cancer is the second leading cause of mortality among all types of cancer in women [1,2,3]
A total of 53 breast cancer tissues and 20 non-tumor breast tissues were collected from hospital, and mRNA expression level of Multidrug resistance-associated protein 1 (MRP1) was detected via real-time polymerase chain reaction (PCR)
We found that MRP1 mRNA expression level was markedly higher in breast cancer tissues than in non-tumor breast tissues (Figure 1B), and this result was consistent with the data obtained from the TCGA database (Figure 1A)
Summary
Breast cancer is the second leading cause of mortality among all types of cancer in women [1,2,3]. Many patients receiving chemotherapy exhibit a poor initial response or gradually develop resistance to chemotherapy, which is defined as multidrug resistance (MDR) and perhaps the greatest obstacle to the treatment of breast cancer. The normal transport between tumor cells and chemotherapeutic agents is destroyed; this mechanism refers to the adaptions that decrease drug uptake and increase drug export, reduce intracellular concentration of the chemotherapeutic agent [7, 8]. Drug transporters play an important role in this type of drug resistance, and MDR-associated protein 1 (MRP1) is one of the most thoroughly studied transporters related to drug resistance [9]
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