Abstract 5954: Dietary sugar promotes breast tumorigenesis partially through upregulating 12 lipoxygenase/PPARd signaling and remodeling breast tumor microenvironment

Abstract

Abstract Ample evidence from epidemiological studies links high-sugar diets with increased breast cancer risk, but the underlying molecular mechanisms remain unclear. We previously reported that sucrose-enriched diets (SED) accelerated breast tumorigenesis in MMTV-ErbB2 mice and promoted the breast tumor growth in orthotopic models of mouse (4T1) or human breast cancer cells (MDA-MB-231) by up-regulating 12-lipoxygenase (12-LOX) and its arachidonate metabolite 12-HETE. In this report, we performed mechanistic studies to determine the role of 12-LOX in SED-induced breast tumorigenesis and also examined the SED effects on remodeling breast tumor microenvironment during SED-induced breast tumorigenesis. We found SED (diet with 125 g/kg sucrose), at a concentration equivalent to the average sugar consumption of American population, significantly increased the 4T1 orthotopic tumor weights by 3.7-fold in average compared to the isocaloric cornstarch control diet group. We obtained data showing that 12-LOX downregulation by CRISPR/Cas9 technology not only significantly reduced tumor incidence and inhibited the tumor growth, but also blocked the SED-promoted breast tumor growth in the MDA-MB-231 cell mouse orthotopic model. We also found that SED increased expression of peroxisome proliferator-activated receptor-delta (PPARd), a lipid nuclear receptor along with its target genes (i. g., LPL, CD36 and SCD1) in 4T1 orthotopic breast tumor tissues. 12-LOX downregulation decreased PPARD expression in MDA-MB-231 cells, while 12-HETE increased PPARd and its target proteins such as PDK4 and ANGPLT4 expression levels in 4T1 cells. Together, these data suggest PPARd as a downstream target gene of 12-LOX. Additionally, our studies showed that SED significantly increased chemokine CCL2 in 4T1 orthotopic tumor tissues and 12-HETE led to higher secreted CCL2 in 4T1 mouse breast cancer cells which was blocked by suppressing PPARd expression. Furthermore, we observed 10-fold higher CD11b+/Ly6G+ cells in SED-induced 4T1 tumor tissues by flow cytometry. Among CD45+ cells, percentage of CD8+ T cells was decreased by 34% in SED-induced 4T1 tumors, and percentages of CD8+/CD69+ (active CD8+ T cells) and CD8+/GrzB+ (effector T cells) were reduced by 78% and 60%, respectively, in SED-induced 4T1 tumors, suggesting SED also led to immune suppressive tumor microenvironment (iTME) during breast tumorigenesis. We further noted that MDSCs, but not macrophages, expressed higher CCR2 in TILs of SED fed tumor than that of cornstarch control diet group, indicating SED induced accumulation of MDSCs is likely mediated by CCL2. In conclusion, our data strongly supports added sugar (sucrose) to accelerate the development and progression of breast cancer, potentially involving up-regulation of the expression of 12-LOX and PPARd as well as iTME. Citation Format: Sharmistha Chakraborty, Xiangsheng Zuo, Venkatesh Hedge, Megan Tran, Yan Jiang, Mihai Gagea, Jagannadha Sastry, Peiying Yang. Dietary sugar promotes breast tumorigenesis partially through upregulating 12 lipoxygenase/PPARd signaling and remodeling breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5954.