Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell-cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.

Keywords: cancer metabolism; reprogramming; signaling pathway; therapeutic signaling; triple-negative breast cancer; tumor microenvironment.

Figure 1

The effect of tumor cells on fibroblast reprogramming. The substances secreted by tumor cells convert normal fibroblasts in the environment into cancer-associated fibroblasts (CAF), which support tumor cell growth, metastasis, and angiogenesis. In CAF cells with increased glycolysis, uptaken glucose is converted to lactate, which is driven by increased efflux to tumor cells through higher MCT4 (monocarboxylate transporter 4) levels. In turn, higher MCT1 levels in tumor cells allow for increased lactate uptake, which is then utilized in the mitochondria via the TCA (tricarboxylic acid) cycle. The amino acids produced by CAF cells offer tumor cells another opportunity for energy utilization. NF: normal fibroblast.

Figure 2

Compounds secreted by adipocytes support tumor growth, angiogenesis and metastasis. Adipocyte-secreted adiponectin, resistin, IGF-1 (insulin-like growth factor 1), and HGF (hepatocyte growth factor) induce tumor growth via activation of the PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) and STAT3 (signal transducer and activator of transcription protein 3) pathway. IGF-1 and HGF also activate the MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathway, together with leptin. HGF, Leptin and VEGF-A (vascular endothelial growth factor A) are involved in angiogenesis, while secreted collagen VI and MMP11 (matrix metalloproteinase 11) play a role in tumor metastasis.

Figure 3

Glycolysis and its relationship with other metabolic pathways in TNBC. Due to higher glucose uptake in TNBC, the pyruvate produced from glucose enters the TCA cycle in mitochondria as Ac-CoA (acetyl coenzyme A). The malate that exits or is converted from pyruvate forms asparagine, whose high expression is associated with poor prognosis in TNBC. The high LDH (lactate dehydrogenase) expression allows elevated lactate efflux, which acidifies extracellular matrix and promotes tumor aggressiveness. Upregulated protein glycosylation via the hexosamine biosynthetic pathway (HBP) and increased NADPH production is described by upregulated pentose phosphate pathway (PPP) and serine synthesis. Additionally, higher fatty acid synthesis (FAO) characterized in TNBC also promotes the energy utilization of tumor cells.

Figure 4

HIF-1α-, glutamine-, and tryptophan-dependent metabolic reprogramming in TNBC. Under physiological conditions, PHD2 (prolyl hydroxylase domain 2) hydroxylates and degrades HIF-1α (hypoxia inducible factor 1 subunit alpha) in an α-KG (alpha-ketoglutarate) and cysteine-dependent manner, thereby inhibiting aerobe glycolysis. In TNBC, PHD2 is inhibited by the cystine/glutamate antiporter xCT and TKT (transketolase), thereby upregulating enzymes and transporters involved in glycolysis. In addition to glycolysis, the entry of amino acids into the TCA cycle also leads to energy gains. In TNBC, the levels of the ASCT2 transporter (responsible for glutamine uptake) and the enzyme GLS, which converts it to glutamate, are upregulated. Meanwhile, catabolism of tryptophan (Trp) is facilitated by overexpressed IDO1. The resulting kynurenine (Kyn) is involved in impairing the immune response and facilitating oncogenic signaling through T cell-derived IFN-γ (interferon γ).

Figure 5

Lipid metabolic reprogramming in TNBC. The key lipogenic enzyme acetyl-CoA carboxylase (ACC) irreversibly catalyzes acetyl-CoA to malonyl-CoA in the mitochondrial membrane, which is an inhibitor of CPT1 and FAO. FAO flux in TNBC is promoted by downregulated ACC, which may also be caused by AMPK (AMP-activated protein kinase) signaling. The resulting increase in cellular acetyl-CoA promotes EMT-inducing Smad2 (SMAD Family Member 2) acetylation and ultimately, activation of EMT pathways and metastasis. Upregulated AKR1B1 in TNBC activates the NF-κB (nuclear factor kappa B) signaling through its accumulated metabolite PGF, which leads to the overexpression of Twist2 and enhances cancer stem cell (CSC) properties in TNBC. Higher asparagine levels are associated with less metastatic potential in TNBC by activation of Twist1 molecule through downregulation of the inhibitor asparaginase.