Mammary epithelial cells have lineage-rooted metabolic identities

Abstract

Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show that mammary populations have cell type-specific metabolic programs. Primary human breast cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of electron transport chain subunits and capacity for oxidative phosphorylation, whereas basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages.Computational analysis indicated that breast cancer subtypes retain metabolic features of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary cells partly explain breast cancer metabolic heterogeneity and rationalize targeting subtype-specific metabolic vulnerabilities to advance breast cancer therapy..

Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments

“…Previous studies have shown that LDH inhibition can suppress glycolysis [153,154] and cell proliferation [155] in BC cell lines. Differences in sensitivity to pharmacological inhibitors targeting glycolysis or electron transport chain (ECT) subunits were evaluated in different metabolic MECs phenotypes by Mahendralingam and colleagues [66]. In this study, the glycolytic phenotype displayed greater sensitivity to inhibitors targeting glucose transporter 1 (GLUT1), hexokinase (HK), LDH, and pyruvate dehydrogenase kinase (PDC), which agrees with results reported by Gong et al [69].…”

“…However, multi-omics-based analyses have been carried out in a reduced number of studies, which probably reflects limited sample availability and/or technical difficulties associated with generating complete multi-omics datasets. Thirteen studies published between 2010 and 2021 have integrated two different omics datasets to identify disease-associated metabolic alterations that could improve the diagnosis and subclassification of BC patients [48,57,[59][60][61][62][63][64][65][66][67][68][69]. Tissue samples represented the most frequently used sample type, with only three studies collecting biofluids (primarily blood).…”

“…Metabolic differences between basal and luminal-like BC phenotypes were recently explored by Mahendralingam and colleagues in a study based on a combined proteomic and transcriptomic analysis of normal mammary epithelial cells (MECs) [66]. The authors identified distinct metabolic phenotypes corresponding to basal, luminal progenitor, and mature luminal cells.…”

Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

“…In addition to the difference in molecular states across the mammary lineages, divergent stress responses and metabolic identities are observed [26,27]. Basal cells isolated from human mammary epithelial cells have low reactive oxygen species (ROS) levels.…”

Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation

“…Altered metabolism is a hallmark of cancer cells 5 . Recent work has elucidated some of the metabolic vulnerabilities of breast cancer subtypes [6][7][8][9] , but how metabolic reprogramming occurs is still poorly understood. The amino acid serine is depleted in the core of melanoma tumors 10 , pancreatic tumors 11 , and in the mammary fat pad 12 , the tissue of origin for breast cancer.…”