Estrogen Enhances the Expression of the Multidrug Transporter Gene ABCG2—Increasing Drug Resistance of Breast Cancer Cells through Estrogen Receptors

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.

FABP7 is a potential biomarker to predict response to neoadjuvant chemotherapy for breast cancer

“…A plethora of preclinical and clinical studies have demonstrated that positive ERα expression in breast cancer cells was associated with decreased sensitivity to chemotherapy [19]. Moreover, ERα contributed drug resistance partly through breast cancer resistance protein (BCRP) [20]. Our results corroborated the previous perspective on the association between ER expression and chemosensitivity, suggesting that ER-positive subtype of breast cancer is more insensitive or resistant to chemotherapy than ER-negative tumors.…”

ABCG2 rs2231142 variant in hyperuricemia is modified by SLC2A9 and SLC22A12 polymorphisms and cardiovascular risk factors in an elderly community-dwelling population

“…However, a previous study in a European population only showed a significant association in males, not in females [21], possibly due to ethnic differences. Estrogen levels can affect ABCG2 expression [22,23], thus we excluded postmenopausal women to eliminate the effect of estrogen on allelic associations with HUA.…”

Effective Cellular Transport of Ortho-Halogenated Sulfonamide Derivatives of Metformin Is Related to Improved Antiproliferative Activity and Apoptosis Induction in MCF-7 Cells

“…The currently ongoing studies have focused mainly on the role of ER in multidrug resistance mainly through efflux transporters, including P-glycoprotein, multidrug resistance-associated protein (MRP) or breast cancer resistance protein (BCRP), which is a major obstacle in the effective therapy of breast cancer [20]. For instance, Chang et al [21] found that estrogen induces the expression of multidrug transporter gene ABCG2 (BCRP) through ERα, making MCF-7 more tolerant to mitoxantrone. Previously, it was also found that estrogen stimulates SLC22A5 (organic cation transporter, OCTN2) expression strongly in an ER-dependent manner and that SLC22A5 expression is associated with the ER status in breast cancer cell lines and breast tissue [22].…”