Abstract 3951: NVP-BEZ235 decreases mutant p53 and affects miR-23a-24a-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. In this study, the AKT-mTOR dual inhibitor, NVP-BEZ235 (called BEZ235 hereafter) was employed to treat two TNBC cell lines, MDA-MB-231 and MDA-MB-468, which serve as TP53 mutation group at different dosages and time points. The results of CCK8, scratch, Transwell chamber and soft agar tests showed that BEZ235 could inhibit cell growth, migration, invasion and transformation abilities of the above TNBC cells. Most importantly, mutant p53 in these TNBC cells decreased significantly with BEZ235 treatment by Western blot. Therefore, we speculated that BEZ235 might inhibit the metastasis of TNBC cells through mutant p53 decline. Furthermore, we observed the autophagy marker LC3I/II conversion elevated obviously by WB, along with the upregulation of LC3 mRNA, which indicated that autophagy was induced after BEZ235 treatment in TNBC cells. To further understand the relationship of autophagy and p53 decrease upon exposure of BEZ235, autophagy inhibitor 3-MA and lentiviral shRNAs embedding ATG5/ATG7 were applied to deplete autophagy, and we found that mutant p53 was still decreased in the cells treated by NVP235 even though the autophagy was inhibited, which indicated that p53 degradation mediated by NVP235 may not relate with autophagy. In order to explore other potential regulatory mechanisms of the p53 downregulation upon BEZ235 exposure, microRNAs were considered to detect in the TNBC cells after treatment. Interestingly, miR-23a-24a-27a cluster was upregulated about 2-fold in TNBC cells after BEZ235 treatment in our study, while tumor growth and metastasis roles were discovered in some previous findings. More studies need to be done to illustrate miR-23a-24a-27a cluster in the TNBC cells treatment with NVP235, as well as the mechanisms with p53 regulation. In conclusion, our results suggest that BEZ235 might inhibit the metastasis abilities of triple-negative breast cancer cells targeting mutant p53 accumulation, 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 p53 mutations. Citation Format: Jiajing Cai, Jingruo Xia, Dan Xiao, Chang Liu, Hebin Liao, Lei Xu, Dongsheng Wang, Xiaolan Guo. NVP-BEZ235 decreases mutant p53 and affects miR-23a-24a-27a to inhibit metastasis in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3951.