Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Estrogen receptor–positive (ERþ) metastatic tumors contribute to nearly 70% of breast cancer–related deaths. Most patients with ERþ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared with other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ERþ liver metastases. We therefore evaluated site specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ERþ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ERþ tumor metastatic sites (liver, lung, and bone), and in vivo, in liver and lung metastasis mouse models. ERþ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregu lated expression of glucose metabolism enzymes in response to fulvestrant. Furthermore, differential ERa activity, but not expres sion, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of fulves trant treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. 1x106 MCF7 Y537S cells resuspended in 1% PBS were injected to ovariectomized, NOD SCID gamma (NSG) immunodeficient female mice via tail vein. Fulvestrant (Sigma) was dissolved in 10% DMSO and 90% corn oil and administrated via intramuscular injection (100 mg/kg) twice a week (Monday, Friday) for four weeks. After six weeks, mice were euthanized and organs were harvested.