Ponnusamy Logeswari, Mahalingaiah Prathap Kumar S, Singh Kamaleshwar P
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79409, USA.
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, TX 79409, USA.
Eur J Pharm Sci. 2017 Jun 15;104:424-433. doi: 10.1016/j.ejps.2017.04.020. Epub 2017 Apr 26.
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.
乳腺癌是女性中最常见的癌症，阿霉素仍是其主要治疗药物。然而，化疗耐药是乳腺癌治疗中的一个主要限制因素。治疗方案和雌激素受体（ER）状态在乳腺癌亚型获得性耐药发展中的作用尚不清楚。因此，本研究的目的是评估乳腺癌细胞中的治疗方案和ER状态是否会影响阿霉素耐药性。为了解决这些问题，分别对ER阳性的MCF-7和三阴性MDA-MB-231乳腺癌细胞系进行持续或间歇暴露于临床相关浓度的阿霉素处理，并评估这两种治疗策略对药物敏感性耐药性的影响。结果显示，间歇治疗而非持续治疗可诱导乳腺癌细胞对阿霉素产生耐药性。与MDA-MB-231细胞相比，MCF-7细胞产生耐药性相对较早且水平较高。在MCF-7细胞耐药发展过程中还观察到上皮-间质转化（EMT）和癌症干细胞样表型的获得。包括药物转运蛋白在内的选定标记基因表达的变化证实了这些细胞对阿霉素耐药。总之，本研究表明，对阿霉素耐药性的获得取决于该药物的治疗方案以及基于雌激素受体的乳腺癌亚型。此外，EMT和干细胞样表型的获得进一步为乳腺癌亚型依赖性化疗耐药发展提供了分子基础。本研究结果对于优化化疗方案以最小化乳腺癌患者的化疗耐药性具有重要的临床意义。
