Abstract
Background: Multidrug resistance is a major obstacle in the successful therapy of breast cancer. Studies have proved that this kind of drug resistance happens in both human cancers and cultured cancer cell lines. Understanding the molecular mechanisms of drug resistance is important for the reasonable design and use of new treatment strategies to effectively confront cancers. Results: In our study, ATP-binding cassette sub-family G member 2 (ABCG2), adenosine triphosphate (ATP) synthase and cytochrome c oxidase subunit VIc (COX6C) were over-expressed more in the MCF-7/MX cell line than in the normal MCF7 cell line. Therefore, we believe that these three genes increase the tolerance of MCF7 to mitoxantrone (MX). The data showed that the high expression of COX6C made MCF-7/MX have more stable on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) expression than normal MCF7 cells under hypoxic conditions. The accumulation of MX was greater in the ATP-depleted treatment MCF7/MX cells than in normal MCF7/MX cells. Furthermore, E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. However, E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor α (ERα) in MCF7 cells. According to the above data, under the E2 treatment, MDA-MB231, which lacks ER, had a higher sensitivity to MX than MCF7 cells. Conclusions: E2 induced the expression of ABCG2 through ERα and the over-expressed ABCG2 made MCF7 more tolerant to MX. Moreover, the over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix. Finally lead to chemoresistance.
Highlights
Breast cancer is the most common cancer in females
Despite the cancer being responsive to a wide variety of single and combination chemotherapy regimens, the response rate to subsequent chemotherapy regimens is significantly decreased due to the development of chemoresistance to multidrug resistance (MDR) [2], which is caused by the multidrug transporter (MDT)
The results show that the expression of adenosine triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2), COX6C, and ATP synthase increased in MCF7/MX cells
Summary
Breast cancer is the most common cancer in females. The annual incidence rate is about 1,150,000 new cases and 370,000 deaths worldwide every year [1]. Despite the cancer being responsive to a wide variety of single and combination chemotherapy regimens, the response rate to subsequent chemotherapy regimens is significantly decreased due to the development of chemoresistance to multidrug resistance (MDR) [2], which is caused by the multidrug transporter (MDT). MDR is a major obstacle in the successful therapy of breast cancer. Multidrug resistance is a major obstacle in the successful therapy of breast cancer. E2 increased the tolerance of MCF7 cells to MX through inducing the expression of ABCG2. E2 could not increase the expression of ABCG2 after the inhibition of estrogen receptor α (ERα) in MCF7 cells. The over-expressed ATP synthase and COX6c affected mitochondrial genes and function causing the over-expressed ABCG2 cells pumped out MX in a concentration gradient from the cell matrix.
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