PT - JOURNAL ARTICLE AU - Qianying Zuo AU - Ayca Nazli Mogol AU - Yu-Jeh Liu AU - Ashlie Santaliz Casiano AU - Christine Chien AU - Jenny Drnevich AU - Ozan Berk Imir AU - Eylem Kulkoyluoglu-Cotul AU - Nicole Hwajin Park AU - David J Shapiro AU - Ben Ho Park AU - Yvonne Ziegler AU - Benita S. Katzenellenbogen AU - Evelyn Aranda AU - John D. O’Neill AU - Akshara Singareeka Raghavendra AU - Debu Tripathy AU - Zeynep Madak Erdogan TI - Targeting metabolic adaptations in the breast cancer–liver metastatic niche using dietary approaches to improve endocrine therapy efficacy AID - 10.1101/2021.09.07.458711 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.09.07.458711 4099 - http://biorxiv.org/content/early/2021/09/07/2021.09.07.458711.short 4100 - http://biorxiv.org/content/early/2021/09/07/2021.09.07.458711.full AB - Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor agonist fulvestrant (Fulv) as standard of care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER agonists remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ 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 ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ERα activity, but not expression, 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 Fulv treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.Competing Interest StatementZME is funded by an investigator-initiated grant from Karyopharm Therapeutics. ZME is a consultant for GSK. ZME is Editor-in-chief for Endocrine and Metabolic Science. BSK has ownership interest in Celcuity, Inc. BHP is a paid consultant for Hologic, EQRx, Jackson Laboratories, Sermonix and is a paid scientific advisory board member with ownership interest for Celcuity. Under separate licensing agreements between Horizon Discovery, LTD and The Johns Hopkins University, BHP is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.