Abstract
Abstract Based on molecular profiling, immunohistochemical detection of ERα, PR and Her2, and morphological evaluation, breast cancer is classified into five subtypes: Luminal A, Luminal B, Her2, Basal-like, and Normal-like. Each subtype has distinct prognosis and treatment response. The luminal A subtype nicely responds to endocrine therapy with a good prognosis, but is less responsive to chemotherapies including paclitaxel. According to a previous study, patients with luminal A breast cancer do not benefit from the addition of paclitaxel to their chemotherapies, but the underlying mechanisms are still not clear. We found that the expression of miRNA miR-100 is dramatically lower in luminal breast cancer cell lines compared to the basal-like subtype. In human breast cancer specimens, while miR-100 expression was downregulated when compared to the matched normal breast tissues, the downregulation in luminal A subtype tumors was more dramatic when compared to other subtypes. We therefore propose that lower levels of miR-100 expression could be responsible for decreased sensitivity of luminal A breast cancer to paclitaxel. To test this hypothesis, we expressed miR-100 in the MCF-7 luminal A breast cancer cell line, and found that expression of miR-100 sensitized MCF-7 cells to paclitaxel treatment by promoting paclitaxel-induced apoptosis and cell cycle arrest. We also suppressed miR-100 expression in the MDA-MB-231 basal-like cell line, and found that miR-100 downregulation desensitized MDA-MB-231 cells to paclitaxel. Tumorigenesis experiments in nude mice further support a role of miR-100 in luminal breast cancer's response to paclitaxel treatment. mTOR, an important player in the PI3K/mTOR signaling pathway, has been identified as a downstream target of miR-100, and combination of rapamycin, a mTOR inhibitor, with paclitaxel enhances the effect of chemotherapy in breast cancer. We found that miR-100 expression inhibited mTOR expression in MCF-7 cells, while suppression of miR-100 increased mTOR expression in MDA-MB-231 cells. These results suggest that miR-100 sensitizes luminal A breast cancer cells to paclitaxel via targeting mTOR. They also provide an explanation for the resistance of luminal A breast cancer to paclitaxel treatment. Citation Format: Baotong Zhang, Ranran Zhao, Yuan He, Xing Fu, Jin-Tang Dong. Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 725. doi:10.1158/1538-7445.AM2015-725
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