Lipid Metabolism Heterogeneity and Crosstalk with Mitochondria Functions Drive Breast Cancer Progression and Drug Resistance

SIMPLE SUMMARY: Metabolic heterogeneity and mitochondrial function are important parameters that might influence therapeutic vulnerabilities and predict the clinical outcomes of cancer patients. While mutations in oncogenes and tumor suppressors can stimulate cell-autonomous metabolic reprogramming, it became clear that the effects of tumor microenvironment (interactions with extracellular matrix and stromal cells and tumor hypoxia) impose a selective pressure on the metabolic preferences of cancer cells. Here, we review recent reports about lipid metabolism heterogeneity in breast cancer progression and therapy response. We describe processes intrinsic to breast cancer cells and extrinsic factors inflicted by the tumor microenvironment that regulate lipid metabolism pathways and breast cancer resistance. ABSTRACT: Breast cancer (BC) is a heterogeneous disease that can be triggered by genetic alterations in mammary epithelial cells, leading to diverse disease outcomes in individual patients. The metabolic heterogeneity of BC enhances its ability to adapt to changes in the tumor microenvironment and metabolic stress, but unfavorably affects the patient’s therapy response, prognosis and clinical effect. Extrinsic factors from the tumor microenvironment and the intrinsic parameters of cancer cells influence their mitochondrial functions, which consequently alter their lipid metabolism and their ability to proliferate, migrate and survive in a harsh environment. The balanced interplay between mitochondria and fatty acid synthesis or fatty acid oxidation has been attributed to a combination of environmental factors and to the genetic makeup, oncogenic signaling and activities of different transcription factors. Hence, understanding the mechanisms underlying lipid metabolic heterogeneity and alterations in BC is gaining interest as a major target for drug resistance. Here we review the major recent reports on lipid metabolism heterogeneity and bring to light knowledge on the functional contribution of diverse lipid metabolic pathways to breast tumorigenesis and therapy resistance.