Metabolic pathways in obesity-related breast cancer

Abstract

This Review focuses on the mechanistic evidence for a link between obesity, dysregulated cellular metabolism and breast cancer. Strong evidence now links obesity with the development of 13 different types of cancer, including oestrogen receptor-positive breast cancer in postmenopausal women. A number of local and systemic changes are hypothesized to support this relationship, including increased circulating levels of insulin and glucose as well as adipose tissue-derived oestrogens, adipokines and inflammatory mediators. Metabolic pathways of energy production and utilization are dysregulated in tumour cells and this dysregulation is a newly accepted hallmark of cancer. Dysregulated metabolism is also hypothesized to be a feature of non-neoplastic cells in the tumour microenvironment. Obesity-associated factors regulate metabolic pathways in both breast cancer cells and cells in the breast microenvironment, which provides a molecular link between obesity and breast cancer. Consequently, interventions that target these pathways might provide a benefit in postmenopausal women and individuals with obesity, a population at high risk of breast cancer.

Fig. 1 |. The breast microenvironment and key drivers of breast cancer in obesity.

Breast tumours are surrounded, and sometimes infiltrated, by breast adipose cells, including adipocytes, adipose stromal cells and immune cells. Obesity is associated with the expansion of adipose tissue and increased release of adipokines as well as with adipocyte dysfunction and cell death, which lead to the recruitment of immune cells and the release of inflammatory mediators. Oestrogen-producing adipose stromal cells respond to changes within the tumour microenvironment by increasing their expression of aromatase, leading to increased oestrogen production. Increased tissue biomass is also associated with both hypoxia and angiogenesis. Obesity-related hyperglycaemia and hyperinsulinaemia provide additional stimuli for breast cancer cell growth. HIF1α, hypoxia-inducible factor 1α; MCP1, monocyte chemoattractant protein 1; VEGF, vascular endothelial growth factor.

Fig. 2 |. Key metabolic pathways in breast cancer.

Several proteins orchestrate the regulation of energy metabolism in proliferating breast cancer cells and cells of the tumour microenvironment. Shifts in the mode of energy production from oxidative phosphorylation to aerobic glycolysis are tightly regulated by a number of proteins, including phosphoinositide 3-kinase (PI3K), RAC serine/threonine-protein kinase (AKT), mammalian target of rapamycin (mTOR) complex 1 (mTORC1), hypoxia-inducible factor 1α (HIF1α), liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p53. Activation of PI3K leads to the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP₃), which binds to and activates AKT. In turn, AKT, via effects on tuberous sclerosis complex 2 (TSC2), activates mTORC1, which leads to the increased translation of several proteins, including HIF1α. AKT and HIF1α stimulate aerobic glycolysis by regulating glucose uptake and glycolytic enzymes. Conversely, binding of AMP to AMPK results in the phosphorylation of AMPK by LKB1 and in the regulation of downstream targets, including the inhibition of fatty acid synthesis, stimulation of fatty acid oxidation and autophagy. AMPK can also phosphorylate (and thereby stabilize) p53. In turn, p53 has been implicated in the downregulation of GLUT1 expression, inhibition of glycolysis and stimulation of oxidative phosphorylation.

Fig. 3 |. Dysregulated metabolic pathways in breast cancer and adipose stromal cells in the context of obesity.

Dysregulation of several metabolic pathways contributes to breast cancer. However, our understanding of the role and regulation of these metabolic pathways in individuals with obesity is still in relative infancy. Several factors, including insulin, hypoxia, leptin and the inflammatory mediators prostaglandin E₂ (PGE₂), tumour necrosis factor (TNF) and IL-6, affect metabolic pathways either in breast cancer cells or in cells of the tumour microenvironment. In breast cancer cells, insulin, leptin and oestradiol (E2) stimulate PI3K–AKT signalling, whereas leptin and E2 suppress AMP-activated protein kinase (AMPK) signalling. Hypoxia induces the stabilization of hypoxia-inducible factor 1α (HIF1α), which (along with obesity-associated mediators) favours a shift towards aerobic glycolysis, increased glucose uptake, stimulation of protein and nucleotide synthesis, and cell proliferation. In adipose stromal cells, leptin, PGE₂, TNF and IL-6 stimulate glucose transporter expression and glucose uptake. PGE₂ and leptin also stimulate HIF1α, suppress LKB1–AMPK signalling and suppress p53 as well as stimulating the expression of aromatase, a crucial enzyme in oestrogen biosynthesis. The net effect of these changes favours the proliferation of cell lineages derived from adipose stromal cells, which could account for the desmoplasia observed in people with obesity. These proliferating adipose stromal cell-derived cells supply lactate and oestrogens that support further tumour cell growth. The effects of obesity on metabolic pathways in immune cells are still poorly characterized. However, hypoxia drives a shift to aerobic glycolysis via effects on HIF2α, and high-fat feeding in preclinical mouse models is associated with suppression of AMPK signalling. These findings suggest that obesity causes a metabolic shift that favours the rapid proliferation of immune cells and supports the increased production of cytokines that promote tumour growth.