Abstract 725: Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR

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