Targeting metabolic adaptations in the breast cancer–liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

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 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.

WNT4 regulates cellular metabolism via intracellular activity at the mitochondria in breast and gynecologic cancers

“…While our analyses of ER-WNT4 signaling support that this pathway underpins fatty acid metabolism in ILC cells, limited data exist on the mechanisms underlying differential metabolic activity, including fatty acid metabolism, in ILC. Notably, recent work from the Madak-Erdogan Laboratory shows that the tumor microenvironment and metastatic niche can dramatically reprogram ER-driven cellular metabolism [41]. Given that ILC metastasize to distinct sites versus IDC (e.g.…”

Per- and Polyfluoroalkyl Substance Exposure Combined with High-Fat Diet Supports Prostate Cancer Progression

“…Treatments were repeated after two days. The effect of PFAS on cell viability was quantified after two days using the WST-1 cell proliferation assay as described [28][29][30][31]. Absorbance readings were measured at 450 nm using a Cytation 5 plate reader (BioTek, Winooski, VT, USA).…”

“…Purified HFDs for our studies (F3282 diet, Bio-Serv, USA), meant to mimic the "Western diet", are high in butterfat (~42% Kcal from fat) and polysaccharide. This diet is commonly used in metabolic syndrome studies [28,32,33].…”