Abstract
This study was conducted to investigate the effect of increased expression of the nuclear transcription factor receptor pregnane X receptor (PXR) on drug resistance of breast cancer cells. Western blotting was used to detect the expression of PXR in breast carcinoma cells. The PXR agonist SR12813 was used to upregulate the expression of PXR. Semi-quantitative polymerase chain reaction was used to detect PXR gene expression in normal and cancerous breast tissues, as well as the expression levels of the drug-resistant genes multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) in breast cancer cells. A Cell Counting Kit-8 assay was used to observe the sensitivity of the breast cancer cells to chemotherapeutic agents. Flow cytometry was used to investigate cell apoptosis. PXR expression was detected in normal and cancerous human breast tissues and in breast cancer cell lines. SR12813 treatment led to an increased expression of PXR protein and an increased expression of drug-resistant genes, MDR1 and BCRP, in MCF-7 and MDA-MB-231 cells. SR12813 pretreatment significantly increased the resistance of MDA-MB-231 cells to docetaxel. A marked increase in resistance to 4-hydroxytamoxifen was also observed in MCF-7 with SR12813 pretreatment. Additionally, we also found that pretreatment with SR12813 led to reduced apoptosis of the two cell strains induced by chemotherapeutic agents. In conclusion, PXR expression has an important effect on the sensitivity to chemotherapy of PXR-positive breast carcinoma. The inhibitory effect of PXR on cell apoptosis may contribute to the drug resistance of breast carcinoma.
Highlights
Breast cancer is the most common malignancy and the second leading cause of cancer‐related mortality among females worldwide [1]
pregnane X receptor (PXR) regulates the expression of a number of downstream targeted genes, which are mostly related to the metabolism and transport of xenobiotics and associated with drug resistance in a number of cancers [4], such as cytochrome P450 (CYP450), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP) and multidrug resistance‐associated protein 2 [5,6,7]
In MDA‐MB‐231 cells treated with 0.3 μM SR12813, the levels of MDR1 mRNA were highest at 12 h
Summary
Breast cancer is the most common malignancy and the second leading cause of cancer‐related mortality among females worldwide [1]. Chemotherapy is one of the most important therapeutic approaches for breast cancer patients; the efficacies of drug treatments on breast cancers are often limited due to the resistance of tumor cells [2]. PXR regulates the expression of a number of downstream targeted genes, which are mostly related to the metabolism and transport of xenobiotics and associated with drug resistance in a number of cancers [4], such as cytochrome P450 (CYP450), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP) and multidrug resistance‐associated protein 2 [5,6,7]. We used SR12813, a potent and selective agonist of hPXR, to upregulate and activate the PXR protein in breast cancer cells, and analyzed the correlation between PXR and drug resistance in breast cancer, this study was designed to explore the formation mechanism of drug resistance of breast cancer cells and provide theoretical basis for clinical chemotherapy
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