Abstract 584: NVP-BEZ235 decreases mutant p53 and downregulates miR-23a-24-27a to inhibit metastasis in breast cancer cells

Abstract

Abstract Nearly half of human cancers harbor TP53 mutations, which are predominantly through missense mutations that result in accumulation of mutant p53 proteins in cancer cells. More and more findings indicate that the mutant p53 proteins acquire gain-of-function abilities to promote carcinogenesis, metastasis, tumor recurrence and chemoresistance. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas, especially the triple negative breast cancer (TNBC),which most easily metastasizes and confers chemoresistance. Therefore targeting TP53 mutation in breast cancer might be another promising approach of therapeutics. Our previous investigation showed that the AKT-mTOR dual inhibitor, NVP-BEZ235(called BEZ235 thereafter), could inhibit AKT-mTOR pathway activation, most interestingly mutant p53 was significantly reduced with BEZ235 treatment(unpublished data). In this study, three TNBC cell lines MDA-MB-231, MDA-MB-436, MDA-MB-468 as TP53 mutation group and MCF-7 as control were employed with BEZ235 treatment at different dosages and time points. We found that AKT-mTOR signaling pathway were highly activated in these TNBC cells but were inhibited obviously after BEZ235 treatment; most importantly, mutant p53 in these TNBC cells decreased significantly, but rare changes were detected in MCF-7 cells with BEZ235 treatment. Interestingly, we found miR-23a-24-27a cluster was about 2 fold upregulation in TNBC cells after BEZ235 treatment while exploring the decline of p53 by detecting microRNAs expression in those cell lines. To address whether BEZ235 could affect the metastasis ability of TNBC cells, cell invasion assay Transwell was used to measure the invasiveness of TNBC cells with BEZ235, and we observed that BEZ235 could inhibit the metastasis of TNBC cells, on the other hand miR-23a-24-27a cluster mimics could also induce the inhibition of metastasis in TNBC cells. Our results suggest that BEZ235 might target mutant p53 accumulation and downregulate miR-23a-24-27a cluster to inhibit the metastasis abilities of triple negative breast cancer cells, which might provide an important direction to further study the breast cancer harboring mutant p53, and also have promising therapeutic benefits for cancer patients carrying such p53 mutations. Citation Format: Dongsheng Wang, Qin Du, Binfeng He, Yibin Deng, Xiaolan Guo. NVP-BEZ235 decreases mutant p53 and downregulates miR-23a-24-27a to inhibit metastasis in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2014-584