Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer

Abstract

Up to one third of all breast cancers are classified as the aggressive HER2-positive subtype, which is associated with a higher risk of recurrence compared to HER2-negative breast cancers. The HER2 hyperactivity associated with this subtype drives tumor growth by up-regulation of mechanistic target of rapamycin (mTOR) pathway activity and a metabolic shift to glycolysis. Although inhibitors targeting the HER2 receptor have been successful in treating HER2-positive breast cancer, anti-HER2 therapy is associated with a high risk of recurrence and drug resistance due to stimulation of the PI3K-Akt-mTOR signaling pathway and glycolysis. Combination therapies against HER2 with inhibition of mTOR improve clinical outcomes compared to HER2 inhibition alone. Here, we review the role of the HER2 receptor, mTOR pathway, and glycolysis in HER2-positive breast cancer, along with signaling mechanisms and the efficacy of treatment strategies of HER2-positive breast cancer.

1H-NMR Plasma Lipoproteins Profile Analysis Reveals Lipid Metabolism Alterations in HER2-Positive Breast Cancer Patients

“…The HER2-positive BC group accounts for approximately 15–25% of all BCs, and it is characterized by high tumour growth rates and aggressive clinical behaviour [ 53 ] linked also to cellular lipids deregulation [ 44 , 54 , 55 ]. The HER2 expression-mediated signalling enhances the activation of specific metabolic networks such as the PI3K/AKT/mTOR pathway hyperactivation, which leads to the up-regulation of both glycolysis and FA synthase enzymes [ 6 , 54 , 55 , 56 , 57 , 58 ]. Besides this lipogenesis phenotype, HER2-tumour cells are also characterized by an increased exogenous FA uptake from the surrounding microenvironment by lipoprotein lipase activity and by the membrane expression of CD36 and LDL receptors (LDLR) [ 10 , 59 , 60 , 61 ].…”

Noncoding RNAs in the Glycolysis of Ovarian Cancer

“…Active glycolysis remains a common feature of cancer metabolism, and metabolic reprogramming increases the expression of critical enzymes and, ultimately, lactate secretion. Lactate in the tumor microenvironment can promote malignant progression and tumor immune escape ( Hashemian et al, 2020 ; Mirzaei and Hamblin 2020 ; Holloway and Marignani 2021 ; Nakagawa et al, 2021 ). Various oncogenes and signaling pathways regulate the glycolytic enzymes to affect the rate of glycolysis ( Almeida et al, 2021 ; Chandel 2021 ).…”

Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

“…MYC signalling also increases the dependency on glutamine metabolism [ 29 ] and uptake [ 30 ] in basal-like tumours, characterized by high glutaminase (GLS) and low GS levels [ 23 ]. Lastly, HER2-enriched tumours generally display a glycolytic phenotype in line with upregulated PKB/AKT-mammalian Target of Rapamycin Complex 1 (mTORC1) signalling [ 31 , 32 , 33 ] and with loss-of-function mutations in Tumour Protein p53 (TP53) [ 34 ]. HER2-enriched tumours also demonstrate enhanced lipid metabolism through increased expression and activity of fatty acid-related genes [ 35 , 36 ].…”