Abstract
Abstract Breast cancer is the most commonly diagnosed invasive cancer in women. Doxorubicin is being the mainstay treatment for solid cancers including breast cancer. However, chemotherapy resistance, either innate or acquired, is a major limitation in breast cancer treatment. The mechanism of resistance as well as the role of estrogen receptor (ER) status in doxorubicin resistance in breast cancer is not clear. Therefore, objective of this study was to determine whether ER status influence the doxorubicin resistance, and to further identify the molecular mechanism in this process. To address this question, ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines were given continuous treatment of clinically relevant concentration of doxorubicin and the pattern of resistance was monitored. Resistance was evaluated using various parameters such as cell count, cell growth and cytotoxicity by MTT assay, cell cycle analysis using flow cytometer. Expression of genes and protein related to cell cycle and cell survival, drug transport, DNA damage repair, metastasis/invasion and epigenetic regulatory complex were measured by qRT- PCR and western blot respectively. Soft agar assay and wound healing assay were performed to determine the anchorage-independent growth and migration potential of resistance cells. Results of MTT assay, and cell cycle revealed that ER-positive MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. This was further confirmed by additional features such as, cancer stem cell markers, epithelial to mesenchymal transition, and increased tumorigenicity in MCF-7 cells than in MDA-MB-231 cells during resistance development. These changes were associated with alteration in drug transporters, cell cycle genes and epigenetic regulatory proteins such as HDAC1 and DNMT1. Pretreatment with demethylating agent 5-aza-deoxycytidine and HDAC inhibitor Trichostatin A significantly resensitized resistance MCF-7 and MDA-MB-231 cells to doxorubicin in comparable to sensitive parental cells. However, this resenstitivty was higher in MCF-7 cells when compared to MDA-MB-231 cells. In summary, result of this study suggests that acquisition of doxorubicin resistance depends on status of estrogen receptor in breast cancer cell lines. Additionally, this differential resistance pattern could be due to differences in epigenetic changes in these two types of breast cancers, thus the acquired resistance could be potentially resensitized using epigenetic therapy Citation Format: Logeswari Ponnusamy, Prathap Kumar Salakatte Mahalingaiah, Kamaleshwar P. Singh. Influence of estrogen receptor status on acquisition of doxorubicin resistance in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2128.
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