Abstract
Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2) on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for treatment of breast cancer patients depending on the serum estrogen levels that varies among pre- and post-menopausal age of the patients.
Highlights
Breast cancer is a disease that includes multiple subtypes with different biological features, and response to clinical treatments varies depending on the subtypes of this disease
The data of MTT assay revealed that doxorubicin and cisplatin treatment resulted in 39.9% and 37% decrease respectively in cell viability of MCF-7E cells as compared to untreated MCF-7E control cells
The most important and novel finding of this study is that the pre-treatment with estrogen significantly enhances the cytotoxic effects of doxorubicin and cisplatin in estrogen responsive breast cancer cells
Summary
Breast cancer is a disease that includes multiple subtypes with different biological features, and response to clinical treatments varies depending on the subtypes of this disease. Breast cancers are classified into subtypes based on several biological characteristics, such as, tumor size and grade, lymph node involvement, estrogen receptors (ER), progesterone receptors (PR) and gene expression profiling, such as human epidermal growth factor receptor 2 (EGFR2) expression [1, 2]. These biological characteristics of breast cancer itself are being used as targets in cancer treatment. Herceptin and lapatinib are used for HER2-positive breast cancer, whereas palbociclib and everolimus are used for ER-positive and HER2-negative breast cancer Hormone therapy is another option because some types of breast cancer are affected by hormone in blood. For women with ER-positive breast cancer, tamoxifen is a drug designed to block estrogen receptors as an anti-estrogen [3,4,5,6]
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