Expanding Roles of De Novo Lipogenesis in Breast Cancer

Abstract

In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.

Lipotoxicity as a Barrier for T Cell-Based Therapies

“…Consequently, suppressed c-Met signaling leads to the impaired downstream activity of the PI3K/AKT pathway and inhibits cell proliferation and apoptosis in these DLBCL cells [ 74 ]. Additionally, overexpression of FASN is not only involved in lipid synthesis but also in driving proliferation via extracellular regulated kinase 1/2 (ERK 1/2) and phosphatidylinositol-3′-kinase (PI3K/AKT), autophagy, DNA repair, lysosome biogenesis, cytoskeletal remodeling and metastasis [ 75 ]. Therefore, it is believed that de novo synthesized FAs are not released into the TME and are rather used for intracellular processes [ 71 , 72 ].…”

Approaches to Measuring the Activity of Major Lipolytic and Lipogenic Enzymes In Vitro and Ex Vivo

“…The DNL pathway is of particular interest as it plays a role in non-alcoholic fatty liver disease [ 173 , 174 ], obesity [ 6 , 175 ], insulin resistance [ 174 ], or cancer [ 176 ]. The process of DNL could be divided into several steps.…”

NFYA promotes the malignant behavior of triple-negative breast cancer through the regulation of lipid metabolism

“…Therefore, there is an urgent need to develop new treatment regimens or identify molecular targets for therapy. Recent remarkable advances in cancer metabolism research have revealed that reprogramming lipid metabolism is one of the hallmarks of cancer 2,3 . It has been reported that lipogenic enzymes are highly expressed in TNBC to obtain membrane phospholipids, signaling molecules, protein modifications, and energy for high proliferation 2,[4][5][6][7] .…”

“…Recent remarkable advances in cancer metabolism research have revealed that reprogramming lipid metabolism is one of the hallmarks of cancer 2,3 . It has been reported that lipogenic enzymes are highly expressed in TNBC to obtain membrane phospholipids, signaling molecules, protein modifications, and energy for high proliferation 2,[4][5][6][7] . Therefore, preclinical and clinical trials targeting lipid metabolism as a therapeutic target are proceeding 3,8,9 .…”