Abstract 1327: Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg

Abstract

Abstract Autophagy genes have been reported to have either tumor promoting or inhibition functions in various cancers, but it is convoluting because of autophagy-independent functions of the respective autophagy genes. We previously reported that suppression of Fip200, an essential autophagy gene, inhibited tumor growth of PyMT driven mammary tumors. To dissect the specific autophagy-dependent function of FIP200 in these tumors, we recently established Fip200 Knock-in PyMT tumor mice with MMTV-Cre (cKI), allowing for conditional inhibition of autophagy in PyMT driven tumors without perturbing the non-autophagy functions of FIP200 . Compared to wild type (WT) tumors, tumor initiation, growth and metastasis were significantly suppressed in both cKI tumors and conditional Fip200 deleted tumors (cKO). Microarray analysis (GSEA) showed that adipogenesis related genes were significantly enriched in WT tumors compared to cKO tumors. The mRNA expression and protein expression of Pparg, one of the master regulators of adipogenesis, were significantly increased with autophagy induction under starvation condition (especially Glucose starvation) in PyMT isogenic cells compared to Fip200 KO and KI cells. Many Pparg target genes were down-regulated in autophagy deficient tumors. Among these, CD36, a free fatty acid (FFA) transporter, was also decreased compared to WT tumors. This suggests that FFA may have important roles as an energy source for PyMT tumor cells to survive under starvation conditions. In conclusion, our results indicate that tumor promotion of PyMT driven tumors was dependent on canonical autophagy. Our future studies will address the detailed mechanism of autophagy dependent tumor growth through metabolic regulation by Pparg. Citation Format: Takako Okamoto, Song Chen, Syn Yeo, Jun-Lin Guan. Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg [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 1327.