Tamoxifen resistance induction results in the upregulation of ABCG2 expression and mitoxantrone resistance in MCF-7 breast cancer cells

by Selleckchem | Oct 07 2023

Cancer endocrine therapy can promote evolutionary dynamics and lead to changes in the gene expression profile of tumor cells. We aimed to assess the effect of tamoxifen (TAM)-resistance induction on ABCG2 pump mRNA, protein, and activity in ER + MCF-7 breast cancer cells. We also evaluated if the resistance to TAM leads to the cross-resistance toward mitoxantrone (MX), a well-known substrate of the ABCG2 pump. The ABCG2 mRNA and protein expression were compared in MCF-7 and its TAM-resistant derivative MCF-7/TAMR cells using RT-qPCR and western blot methods, respectively. Cross-resistance of MCF-7/TAMR cells toward MX was evaluated by the MTT method. Flow cytometry was applied to compare ABCG2 function between cell lines using MX accumulation assay. ABCG2 mRNA expression was also analyzed in tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) breast tumor tissues. The levels of ABCG2 mRNA, protein, and activity were significantly higher in MCF-7/TAMR cells compared to TAM-sensitive MCF-7 cells. MX was also less toxic in MCF-7/TAMR compared to MCF-7 cells. ABCG2 was also upregulated in tissue samples obtained from TAM-R cancer patients compared to TAM-S patients. Prolonged exposure of ER + breast cancer cells to the active form of TAM and clonal evolution imposed by the selective pressure of the drug can lead to higher expression of the ABCG2 pump in the emerged TAM-resistant cells. Therefore, in choosing a sequential therapy for a patient who develops resistance to TAM, the possibility of the cross-resistance of the evolved tumor to chemotherapy drugs that are ABCG2 substrates should be considered. Prolonged exposure of MCF-7 breast cancer cells to tamoxifen can cause resistance to it and an increase in the expression of the ABCG2 mRNA and protein levels in the cells. Tamoxifen resistance can lead to cross-resistance to mitoxantrone.

Comments:

The passage you provided describes a study that aimed to investigate the effects of tamoxifen (TAM) resistance on the expression and activity of the ABCG2 pump in ER+ MCF-7 breast cancer cells. The researchers also evaluated whether TAM resistance led to cross-resistance to mitoxantrone (MX), which is known to be a substrate of the ABCG2 pump.

The study compared the levels of ABCG2 mRNA and protein expression in MCF-7 cells (sensitive to TAM) and their TAM-resistant derivative, MCF-7/TAMR cells. The researchers used RT-qPCR and western blot methods to assess mRNA and protein expression, respectively. They found that the levels of ABCG2 mRNA, protein, and activity were significantly higher in the TAM-resistant MCF-7/TAMR cells compared to the TAM-sensitive MCF-7 cells.

To determine if TAM resistance resulted in cross-resistance to MX, the researchers used the MTT method to evaluate the toxicity of MX in both cell lines. They observed that MX was less toxic in MCF-7/TAMR cells compared to MCF-7 cells, suggesting the development of cross-resistance.

The study also analyzed ABCG2 mRNA expression in tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) breast tumor tissues obtained from patients. The results showed that ABCG2 expression was higher in TAM-R tumor tissues compared to TAM-S tumor tissues.

Based on these findings, the study suggests that prolonged exposure of ER+ breast cancer cells to TAM and the clonal evolution driven by the selective pressure of the drug can result in increased expression of the ABCG2 pump in TAM-resistant cells. Consequently, when selecting sequential therapy for a patient who develops TAM resistance, it is important to consider the possibility of cross-resistance to chemotherapy drugs that are substrates of the ABCG2 pump.

In summary, this study highlights the potential consequences of TAM resistance in breast cancer cells, including increased expression of the ABCG2 pump and the development of cross-resistance to other drugs such as mitoxantrone. These findings have implications for the design of treatment strategies for patients who become resistant to TAM.