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 antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in the liver is associated with reduced overall survival compared to 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 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. Implications: 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.…”

Mechanisms of drug resistance in breast cancer liver metastases: Dilemmas and opportunities

“… 70 Zuo et al., reported a fasting-mimicking diet has been demonstrated to block a glucose surge and reduce glycogen accumulation in the liver, so it may improve the therapeutic effect of fulvestrant in BCLM patients. 71 …”

The emerging role of fasting-mimicking diets in cancer treatment

“…[53] Recently, a dietary intervention targeting glucose metabolism and glycogen deposition improved the response to fulvestrant in patients with estrogen receptor–positive breast cancer with liver metastasis. [54]…”

“…[53] Recently, Volume 8 Issue 2 June 2023 journals.lww.com/jno a dietary intervention targeting glucose metabolism and glycogen deposition improved the response to fulvestrant in patients with estrogen receptor-positive breast cancer with liver metastasis. [54] Vitamin C is an important antioxidant and has been suggested as an alternative anticancer agent. This vitamin alone is unlikely to prevent cancer development, but an FMD-sensitized KRAS-mutant tumors to vitamin C by downregulating the stress-induced protein, HO-1.…”