Abstract
Simple SummaryBreast 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.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.
Highlights
Breast cancer is the most frequently diagnosed cancer among women worldwide [1,2], which makes it one of the leading causes of cancer death
In addition to metabolic changes driven by genetic alterations, breast cancer cell metabolism can adapt to tumour extrinsic factors that arise from their microenvironment through a process called metabolic flexibility [11]
We have discussed the tumour intrinsic and extrinsic factors that contribute to the inter- and intra-tumour metabolic heterogeneity of breast cancer as well as the tumour extrinsic factors that modulate metabolic flexibility and the consequences leading to pro-tumorigenic adaptive capacities
Summary
Breast cancer is the most frequently diagnosed cancer among women worldwide [1,2], which makes it one of the leading causes of cancer death. In addition to metabolic changes driven by genetic alterations, breast cancer cell metabolism can adapt to tumour extrinsic factors that arise from their microenvironment through a process called metabolic flexibility [11]. The heterogeneous metabolic profiles resulting from intrinsic and extrinsic factors in breast tumours support pro-tumorigenic functions and contribute to the high variability of prognosis and treatment response (Figure 1). The objectives of this review are to discuss the various mechanisms that contribute to the heterogeneity of breast cancer metabolism and to highlight the significant role of metabolic flexibility in supporting tumour progression and adaptive capacity. Metabolic heterogeneity leads to improved pro-tumorigenic adaptive include distinct prognosis and variability in treatment response across and/or within tumours. Figure created with BioRender.com heterogeneity leads to improved pro-tumorigenic adaptive capacities that support breast tumour progression, drug (AI22YV1EAE).
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