Abstract
MicroRNAs (miRNAs) are small non-coding RNAs which have been considered as major players in the process of carcinogenesis and drug responsiveness of breast cancer. In this study, we aimed to investigate the expression pattern of let-7a and miR-205 tumorsuppressor miRNAs in breast cancer cell lines under treatment with paclitaxel. The half maximal inhibitory concentration (IC50) of paclitaxel was determined for 4 breast cancer cell lines, including MCF-7, MDA-MB-231, SKBR-3, and BT-474 by an MTT assay. The expression level of let-7a and miR-205, and their targets, K-RAS and HER3, was determined before and after treatment with paclitaxel, using quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). After treatment, the expression level of both let-7a and miR-205 was significantly increased in HER2- overexpressing cell line BT-474 (26.4- and 7.2-fold, respectively). In contrast, the HER2-negative cell lines MCF-7 and MDA-MB-231 showed a significantly decreased expression of both let-7a (30.3- and 13.5-fold, respectively) and miR-205 (20- and 18.1-fold, respectively). Controversially, SKBR-3 revealed a significantly decreased expression of both let-7a (1.3-fold) and miR-205 (1.3-fold). The expression level of K-RAS as a target of let-7a decreased in all cell lines significantly, but the pattern of alteration in the expression level of HER3 as a target of miR-205 in all cell lines was the reverse of the pattern of alteration in the expression level of miR-205. Our results confirmed a better response of HER2-overexpressing breast cancer to paclitaxel at the miRNA level. One putative reason could be the upregulation of tumor-suppressor miRNAs after treatment with paclitaxel. On the other hand, HER2-negative breast cancer cell lines showed a significantly decreased expression of tumor-suppressor miRNAs, a putative mechanism of resisting the therapy.
Highlights
During the past decades, breast cancer has been the most frequent type of carcinoma and the second most fatal cancer among women worldwide
The expression level of both let-7a and miR-205 was significantly increased in HER2overexpressing cell line BT-474 (26.4- and 7.2-fold, respectively)
The expression level of K-RAS as a target of let-7a decreased in all cell lines significantly, but the pattern of alteration in the expression level of HER3 as a target of miR-205 in all cell lines was the reverse of the pattern of alteration in the expression level of miR-205
Summary
Breast cancer has been the most frequent type of carcinoma and the second most fatal cancer among women worldwide. Both the prevalence and mortality of breast cancer is increasing[1]; it has been estimated that 249,260 new cases and 40,890 deaths due to breast cancer will occur in the United States in 2016.2 Breast cancer occurs as a result of a collection of genetic alterations and environmental factors.[3] Among the well-known genetic loci related to breast cancer are: breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), human epidermal growth factor receptor-2 (HER-2) and tumor protein p53 (TP53).[4,5,6] Dietary habits like consuming fat-rich foods, presence of chemical substances in food, long exposure to estrogen, e.g., excessive use of steroids, and use of alcohol are examples of environmental risk factors.[3,7] Breast cancer is a heterogenic disease which includes molecular subtypes, characterized by immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2 These molecular subtypes differ in response to treatment, progression and preferential organs to metastasis.[8,9] The treatment approaches for breast cancer are surgery, radiation and chemotherapy with different agents, such as taxanes, anthracyclines, hormone-based drugs, and targeted therapy with monoclonal antibodies.[10]. MicroRNAs (miRNAs) are small non-coding RNAs which have been considered as major players in the process of carcinogenesis and drug responsiveness of breast cancer
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