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

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.

Automated summary

Cancer endocrine therapy can promote evolutionary dynamics and lead to changes in gene expression in tumor cells, as demonstrated by the resistance induction to tamoxifen (TAM) in ER+ MCF-7 breast cancer cells. This resistance resulted in increased expression and activity of the ABCG2 pump, and also led to cross-resistance to mitoxantrone (MX), a known ABCG2 substrate. These findings were consistent in both cell lines and tumor tissues from TAM-resistant patients, highlighting the importance of considering ABCG2-mediated cross-resistance when choosing sequential therapies for TAM-resistant patients.