Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

SIMPLE SUMMARY: Breast cancer comprises a wide variety of cancer cells that present distinct phenotypes and develop various nutrient dependencies to grow and survive in stressful microenvironments. Breast cancer treatment remains challenging due to resistance to anticancer drugs, recurrence, and dissemination of cancer cells to secondary sites. Here, we review the diverse dependencies of breast cancer cells on various metabolites and metabolic pathways that support breast tumour progression. Moreover, we explore potential strategies to use metabolic dependencies as a therapeutic target for breast cancer patients. 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.