Abstract A09: Diet-induced obesity promotes breast cancer progression by LPA-signaling-mediated functional changes of mitochondria and angiogenesis
Authors: Yuan Ye , Kohlenberg Jacob D. , Chen Yiliang , Komas Steve , Xin Gang , Yuan Gloria , Cui Weiguo , Wu Shiyong , Ren Bin 
Published: May 2015

Abstract
Despite insight that obesity greatly increases cancer risk including breast cancer (BC) is supported by epidemiological studies, the direct link and mechanisms by which obesity increases BC risk remain largely unknown. Nutritional obesity is associated with a prediabetic state characterized by alteration in glucose homeostasis. The increased glucose level may aid cancer cells in generating metabolic advantage. Obesity is also accompanied by an autotaxin (ATX) mediated synthesis of bioactive signaling phospholipid or lysophosphatidic acid (LPA). ATX and plasma LPA are up-regulated in diet-induced obese (DIO) mice. We have shown that LPA stimulated angiogenesis via turning off CD36 antiangiogenic switch in endothelial cells (ECs) via protein kinase PKD-1 pathway. We hypothesize that obesity-derived LPA is a key bona fide tumor promoter by modifying mitochondrial bioenergetic metabolism and stimulating BC angiogenesis in response to high glucose. Using Seahorse Bioscience Extracellular Flux Analyzer, we discovered that LPA enhanced mitochondrial respiration of human breast adenocarcinoma cell MDA-MB231 transduced with wild type PKD-1 (PKD-WT) under high glucose conditions. LPA exposure significantly changed oxygen consumption rate (OCR), ATP linked OCAR but not extracellular acidification rate (ECAR) in cells exposed to high glucose. However, the change of OCR was attenuated by a selective PKD inhibitor CID755673. Furthermore, when exposed to conditional medium from human microvascular endothelial cells (HMVECs), MDA-MB231 overexpressing PKD-WT showed lower levels of basal OCR, ATP linked OCAR and ECAR compared with control medium. Obesity-derived LPA also inhibited CD36 expression in tumor-associated ECs and promoted BC cell growth, which was partially abolished by ATX inhibitor. Intriguingly, CID755673 inhibited clonogenic survival of MDA-MB231. To determine in vivo mechanisms of obesity-derived LPA, we established a syngeneic BC model by subcutaneously implanting E0771 adenocarcinoma in female C57BL/6J mice. DIO greatly promoted BC development in mice, demonstrated by huge tumors in DIO but not in control mice. DIO mice also showed increase in LPA receptor 1 in tumor endothelium, with robust angiogenesis and extensive bleeding inside tumor. Additionally, a high level of PD-1 expression was found in CD8 T cells inside the tumor in obese mice, implicating diet-induced obesity leads to T cell dysfunction. Our data suggests that LPA is a key player in BC angiogenesis and development but it is not the only mediator responsible for obesity-induced tumor progression. LPA-stimulated tumor progression may be associated with alternation of bioenergetic function via PKD signaling under high glucose conditions. DIO-enhanced LPA signaling may contribute to EC CD36 downregulation and dysregulated mitochondrial functions, leading to proangiogenic responses in tumor microenvironment. DIO-stimulated LPA signaling could modulate switch between mitochondrial oxidative phosphorylation and aerobic glycolysis in both BC and tumor endothelium. Targeting LPA-PKD-metabolic signaling axis may provide a novel therapeutic strategy.
Citation Format: Ye Yuan, Jacob D. Kohlenberg, Yiliang Chen, Steve Komas, Gang Xin, Gloria Yuan, Weiguo Cui, Shiyong Wu, Bin Ren. Diet-induced obesity promotes breast cancer progression by LPA-signaling-mediated functional changes of mitochondria and angiogenesis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A09. doi:10.1158/1538-7445.CHTME14-A09