Treatment schedule and estrogen receptor-status influence acquisition of doxorubicin resistance in breast cancer cells

Abstract

Breast cancer is the most common cancer in women for which doxorubicin is still the mainstay treatment. However, chemotherapy resistance is a major limitation in breast cancer treatment. Role of treatment schedule and estrogen receptor (ER) status in subtypes of breast cancers in acquired resistance development is not clear. Therefore, objective of this study was to evaluate whether the treatment schedule and ER status in breast cancer cells influence the doxorubicin resistance. To address these questions, ER-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines were given either continuous or intermittent exposure with clinically relevant concentration of doxorubicin and the influence of these two treatment strategies on resistance to drug sensitivity was evaluated. Results revealed that intermittent treatment but not the continuous treatment induced resistance in breast cancer cells against doxorubicin. MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. Acquisition of epithelial to mesenchymal transition (EMT) and cancer stem cell-like phenotype was also observed during resistance development in MCF-7 cells. Changes in the expression of selected marker genes including drug transporters confirmed doxorubicin resistance in these cells. In summary, this study suggests that acquisition of resistance against doxorubicin depends on the treatment schedule of this drug as well as the estrogen receptor-based subtypes of breast cancer. Additionally, acquisition of EMT and stem cell-like phenotype further provided a molecular basis for breast cancer subtype-dependent chemotherapeutic resistance development. Findings of this study will have significant clinical implications in optimizing the chemotherapy schedule to minimize chemoresistance in breast cancer patients.