Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

Abstract

Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.

RIP140 inhibits glycolysis-dependent proliferation of breast cancer cells by regulating GLUT3 expression through transcriptional crosstalk between hypoxia induced factor and p53

“…Therefore, RIP140-deficiency leads to a high metabolically active phenotype, with both high glycolysis and high OxPhos. This phenomenon, observed in breast cancer and other cancer types, could provide more flexibility to survive and could contribute to tumor heterogeneity [38,39]. Furthermore, our data demonstrate that down-regulating Glut3 expression provoked the inhibition of RIP140-deficient cell proliferation.…”

Take metabolic heterogeneity into consideration when applying dietary interventions to cancer therapy: A review

“…Current methods measuring metabolic activity in cancer, such as metabolite detection of tumor interstitial fluid (TIF), only represent an average level in the extracellular fluid and thus fail to capture the heterogeneity between different subdomains [ 124 ]. The primary data obtained using state-of-the-art technologies have identified substantial spatial metabolic heterogeneity within single tumors, suggesting that assigning a specific metabolic profile to a single tumor may overlook important aspects of tumor metabolism [ 125 ]. The vascularization variations between subdomains of a cancer, which make oxygen and nutrient availability different for cancer cells within different subdomains, have been well characterized.…”

Deciphering the Chemotherapeutic Role of the Aryl Hydrocarbon Receptor Antagonist Resveratrol against the High-Penetrance Genes of Triple-Negative Breast Cancer

“…Currently, breast cancer (BC) persists as the dominant cause of malignancy-related deaths among women worldwide. It has surpassed lung cancer as the highest and most commonly diagnosed malignancy globally and second in terms of cancer mortality in the US. , The tremendous molecular variability of BC may be partially attributed to the ambiguity of the three main hormone receptors, viz., estrogen (ER), human epidermal growth factor 2 (HER2), and progesterone (PR). − Based on the expression profile of the endocrine receptors, hormone-responsive luminal BC, receptor-deprived triple-negative BC (TNBC), and HER2-enriched BC are categorized as the primary subclasses of mammary malignancy. Substantial breakthroughs in clinical oncology have succeeded in reducing the global hormone-receptive BC mortality rate; TNBC is specifically linked to extremely adverse prognosis.…”