The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

Abstract

Within heterogeneous tumors, cancer stem cell (CSC) populations exhibit the greatest tumor initiation potential, promote metastasis, and contribute to therapy resistance. For breast cancer specifically, CSCs are identified by CD44 high CD24 low cell surface marker expression and increased aldehyde dehydrogenase activity. In general, bulk breast tumor cells possess altered energetics characterized by aerobic glycolysis. In contrast, breast CSCs appear to have adaptive metabolic plasticity that allows these tumor-initiating cells to switch between glycolysis and oxidative phosphorylation, depending on factors present in the tumor microenvironment (e.g., hypoxia, reactive oxygen species, availability of glucose). In this article, we review the regulatory molecules that may facilitate the metabolic plasticity of breast CSCs. These regulatory factors include epigenetic chromatin modifiers, non-coding RNAs, transcriptional repressors, transcription factors, energy and stress sensors, and metabolic enzymes. Furthermore, breast cancer cells acquire CSC-like characteristics and altered energetics by undergoing epithelial-mesenchymal transition (EMT). This energy costly process is paired with reprogrammed glucose metabolism by epigenetic modifiers that regulate expression of both EMT and other metabolism-regulating genes. The survival advantage imparted to breast CSCs by metabolic plasticity suggests that targeting the factors that mediate the energetic switch should hinder tumorigenesis and lead to improved patient outcomes.

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

“…Multiple regulatory factors including metabolic enzymes promoted the metabolic plasticity of stem cells in breast cancers. The metabolism-regulating genes and epigenetic factors that regulate glucose metabolism might also regulate the expression of EMT (49). An enhanced Warburg effect was observed in metastatic prostate cancers (44).…”

LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer

“…For this reason, we explored phenotypic and functional characteristics of lncRNA PART1 in breast cancer, which has been previously implicated in both oncogenic and tumor suppressive function in other cancer types including prostate, esophageal, lung, colorectal and glioblastoma. In esophageal and lung cancers, PART1 is oncogenic [ 24 , 25 , 28 , 64 ]. Some evidence suggests that PART1 may play a similar oncogenic role in breast cancer [ 31 ].…”

EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents?

“…CSCs are cancer cell subpopulations endowed with great adaptive potential which allows them to survive therapy-induced stress and to drive tumor relapse and metastasis, as an effect of molecular adaptive processes fueling clonal rearrangements of cancer cell subpopulations. CSCs are characterized by the expression of stemness genes and detoxifying systems and by great metabolic plasticity [ 144 , 145 , 146 , 147 ]. Epithelial to mesenchymal (EMT) transition is believed to play a role in fueling the emergence of CSC subpopulations [ 148 ].…”