Abstract 87: Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast cancer cells

Abstract

Abstract Breast cancer is the leading cause of cancer related mortality in women. Chemotherapy resistance is a major limitation in clinical treatment of breast cancer. Mounting evidence implicates the epigenetic aberrations in acquired chemoresistance. However, the influence of treatment schedules and associated epigenetic changes on acquisition of doxorubicin resistance in breast cancer is not clear. Therefore, objective of this study was to evaluate the impact of treatment schedules on acquisition of doxorubicin resistance and the molecular mechanistic basis of this process in breast cancer cells. To address this question, two different treatment strategies viz, continuous exposure and intermittent exposure were used to generate doxorubicin resistant cells lines from ER-positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. The level of resistance against doxorubicin and the temporal sequence of molecular changes associated with the resistance phenotype were evaluated at 4 months and 18 months’ following exposure to doxorubicin. Results revealed that intermittent exposure to doxorubicin resulted in significantly higher level of resistance as compared to continuous exposure. ER-positive MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. Additionally, the resistance to doxorubicin-induced cytotoxicity was associated with transient acquisition of EMT and CSC-like phenotype in breast cancer cells around 4 months following doxorubicin. Gene and protein expression analysis further revealed temporal changes in the expression of epigenetic regulatory genes and histone modifications respectively. The temporal changes in expression of genes were positively correlated with doxorubicin exposure time during resistance development. In summary, the result of this study for the first time suggests that the treatment schedules influence the acquisition of doxorubicin resistance potentially through epigenetic mechanisms. The findings of this study will be helpful in chemotherapy of breast cancer to achieve the best clinical result Note: This abstract was not presented at the meeting. Citation Format: Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah, Kamaleshwar P. Singh. Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 87. doi:10.1158/1538-7445.AM2017-87