Recent insights into the effects of metabolism on breast cancer cell dormancy

Abstract

Breast cancer (BC) remains the most common cancer, as well as the leading cause of cancer mortality in women worldwide [1]. Approximately 30% of patients with early-stage BC experience metastasis or a recurrent form of the disease [2]. The phenomenon of BC dormancy, where metastasised cancer cells remain in a quiescent phase at their disseminated location and for unknown reasons can become actively proliferative again, further adds to BC’s clinical burden with treatment at this secondary stage typically proving futile. An emerging avenue of research focuses on the metabolic properties of dormant BC cells (BCCs) and potential metabolic changes causing BCCs to enter/exit their quiescent state. Here we explore several studies that have uncovered changes in carbon metabolism underlying a dormant state, with conflicting studies uncovering shifts towards both glycolysis and/or oxidative phosphorylation. This review highlights that the metabolic states/shifts of dormant BCCs seem to be dependent on different BC subtypes and receptor status; however, more work needs to be done to fully map these differences. Building on the research that this review outlines could provide new personalised therapeutic possibilities for BC patients.

In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence

“…This may specifically compound the effects of the Etomoxir treatment, though future work is required to substantiate this potential additional mechanism of action. Given the observation of prolonged dormancy in tumor cells undergoing increased fatty acid synthesis and elongation, our work supports growing evidence of the importance of lipid metabolism in the context of dormancy and recurrence 61 , 62 .…”

“…Further, several factors including genetic, epigenetic, microenvironmental pathways, and metabolic pathways can all play a role in tumor dormancy and recurrence and not all of these observed in an induced Her2+/Neu model can faithfully model those seen in clinical recurrence 54 – 56 , 61 , 73 , 74 . Finally, it is important to note a clear distinction between the Her2+/Neu oncogene ablation model and clinical Her2+ tumors.…”

SP and KLF Transcription Factors in Cancer Metabolism

“…During breast cancer development and progression, there is an increase in the metabolism of glucose, lipids, and amino acids [ 91 ]. In breast cancer, there is often a shift toward glycolytic metabolism to supply the cell with higher amounts of ATP [ 92 ]. This increase in glycolysis is accompanied by the accumulation of protons in the cell, which could cause cell death if acid extrusion is not induced to maintain homeostasis.…”

Extracellular vesicle cargo metabolome changes in response to the mesenchymal stromal cell microenvironment and influences cell quiescence and activation in a human breast cancer cell model

“…The deregulation of cellular energetics is a hallmark of cancer (64). Yet, research into the metabolic properties of dormant BCCs is limited, and the studies performed to date are contradictory (35). For example, several reports have concluded that a shift in BCCs towards glycolysis is responsible for BCC dormancy, whereas others have reported that a BCC shift towards OXPHOS induces dormancy (35,(67)(68)(69)(70).…”

“…Specifically, we compared the interactions of a 3D breast cancer cell (MCF7) spheroid model with MSC-EVs isolated from: (a) a standard MSC monolayer, which we propose induces a quiescent BCC phenotype (pQ-EVs); and (b) a regenerative scratch wound MSC model, which we propose activates BCCs (pA-EVs). The reactivation of dormant BCCs at metastatic sites is hypothesised to be a mechanism of both early and late BC recurrence, where the elapsed time after cancer recurrence upon successful treatment depends on the BC subtype (32)(33)(34)(35). For instance, triple negative BC patients typically experience cancer recurrence after 1-2 years.…”