Abstract 3601: Dietary phosphatidylcholine depletion reduces tumor development independent of autotaxin inhibition in hyperlipidemic mouse models of breast cancer
Authors: Onono Fredrick O. , Adindu Ebubechi , Yan Baoxiang , Soman Sony , Hammill Courtney , Morris Andrew J. 
Published: August 2019

Lysophosphatidic acid (LPA) is a pleiotropic growth-factor lysophospholipid that promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The main precursor for LPA, lysophosphatidylcholine (LPC) is derived majorly from the highly abundant phosphatidylcholine (PC). Hydrolysis of LPC to the circulating LPA is catalyzed by the enzyme autotaxin (ATX), a secreted lysophospholipase D. We investigated the effects of altering dietary intake of PC and pharmacological inhibition of ATX on breast cancer development in mice. To formulate diets with defined PC levels we used tandem mass spectrometry to measure the concentration of PC in various components of fat used to manufacture rodent diets. We determined that casein is the main source of PC when present in rodent diets. High fat diets (60% kcal fat) were formulated with casein (high PC) or amino acids in place of casein (low PC). To study the effects of these diets on breast cancer development, six-week old female C57Bl6 low density lipoprotein receptor knockout mice (LDLr-/-) were fed high fat diets for 12 weeks. Subsequently, E0771 syngeneic mammary cells were injected into the inguinal mammary fat pads of mice fed continuously on high fat diets. At the time of tumor cell inoculation, the animals were divided into groups to either receive daily dosage of a novel potent ATX inhibitor or vehicle control. Primary tumor growth was monitored using orthogonal caliper measurements and tumor volumes estimated from width2 × length/2. The number of metastatic nodules in the lungs were counted after staining with India ink. In high fat diet mouse models of breast cancer we observed that feeding mice with diets in which casein is replaced with amino acids decreases primary tumor growth. Contrary to our expectation, treatment with a potent ATX inhibitor resulted in no significant effect on primary tumor growth and an increased number of metastatic nodules compared with vehicle-treated mice. Moreover, treatment with the ATX inhibitor reversed the beneficial effects of casein replacement and instead resulted in enhanced tumor growth and metastasis. These studies suggest that dietary casein promotes primary tumor growth in the hyperlipidemic E0771 models of cancer and that targeting ATX inhibition is not efficacious in these models. Our results show that under certain hyperlipidemic conditions consumption of dietary casein can promote primary tumor growth. We also provide evidence emphasizing the need for further investigation in ascertaining the impact and utility of ATX inhibitors in breast cancer treatment.

Citation Format: Fredrick O. Onono, Ebubechi Adindu, Baoxiang Yan, Sony Soman, Courtney Hammill, Andrew J. Morris. Dietary phosphatidylcholine depletion reduces tumor development independent of autotaxin inhibition in hyperlipidemic mouse models of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3601.