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

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posted on 2023-04-03, 20:07 authored by Qianying Zuo, Ayca Nazli Mogol, Yu-Jeh Liu, Ashlie Santaliz Casiano, Christine Chien, Jenny Drnevich, Ozan Berk Imir, Eylem Kulkoyluoglu-Cotul, Nicole Hwajin Park, David J. Shapiro, Ben Ho Park, Yvonne Ziegler, Benita S. Katzenellenbogen, Evelyn Aranda, John D. O'Neill, Akshara Singareeka Raghavendra, Debu Tripathy, Zeynep Madak Erdogan
Supplementary Figure from Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Funding

University of Illinois

Office of the Vice Chancellor for Research

Future Interdisciplinary Research Endeavors

Cancer Center at Illinois

National Institute of Food and Agriculture

U.S. Department of Agriculture

Cancer Scholars for Translational and Applied Research

Cancer Center at Illinois and the Carle Cancer Center

NIH

Susan G. Komen Foundation

Breast Cancer Research Foundation

Breast Cancer Research

History

ARTICLE ABSTRACT

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 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 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 fulvestrant. 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 fulvestrant 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.

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