Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

Abstract

Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF‐7 and MDA‐MB‐231 cell metabolism and promotes proliferation and migration. Since adipocytes are FA‐rich, and these FAs are transferred to BrCa cells, we sought to elucidate the FA metabolism of BrCa cells and their response to FA‐rich environments. MCF‐7 and MDA‐MB‐231 cells incubated in serum‐containing media supplemented with FAs accumulate extracellular FAs as intracellular triacylglycerols (TAG) in a dose‐dependent manner, with MDA‐MB‐231 cells accumulating more TAG. The differences in TAG levels were a consequence of distinct differences in intracellular partitioning of FAs, and not due to differences in the rate of FA uptake. Specifically, MCF‐7 cells preferentially partition FAs into mitochondrial oxidation, whereas MDA‐MB‐231 cells partition FAs into TAG synthesis. These differences in intracellular FA handling underpin differences in the sensitivity to palmitate‐induced lipotoxicity, with MDA‐MB‐231 cells being highly sensitive, whereas MCF‐7 cells are partially protected. The attenuation of palmitate‐induced lipotoxicity in MCF‐7 cells was reversed by inhibition of FA oxidation. Pretreatment of MDA‐MB‐231 cells with FAs increased TAG synthesis and reduced palmitate‐induced apoptosis. Our results provide novel insight into the potential influences of obesity on BrCa biology, highlighting distinct differences in FA metabolism in MCF‐7 and MDA‐MB‐231 cells and how lipid‐rich environments modulate these effects.

Glucose Favors Lipid Anabolic Metabolism in the Invasive Breast Cancer Cell Line MDA-MB-231

“…Moreover, palmitate in MCF7 cells is set aside for mitochondrial oxidation. Whereas palmitate uptake has been found to be similar in MCF7 and MDA-MB-231 cell lines, only MDA-MB-231 cells, in which palmitate has a different metabolic fate, underwent apoptosis after palmitate exposure [43]. Whether glucose is involved in the pro-apoptotic effect of palmitate in MDA-MB-231 cells or if palmitate also triggers an apoptotic response in other invasive tumor cell lines needs to be further researched.…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Additionally, adipocyte-derived FFAs can also be incorporated into phospholipids and esterified with cholesterol to produce cholesteryl esters in cell membranes (73,74) to induce lipid-saturated membranes. This is further supported by the increased amount and size of lipid droplets found in breast cancer tumors, specifically more aggressive phenotypes (6,73). Therefore, it may also be plausible that the increased tumor volume in the HFD fed groups maybe be as a result of membrane lipid saturation and lipid droplet deposition within tumor tissue.…”

“…This is evident by an upregulation of various enzymes catalyzing de novo FA synthesis in breast cancer cells i.e., Acetyl-CoA carboxylase (ACC), FAS and SCD-1 (13,70,71). Supporting evidence includes increased exogenous lipid utilization, where breast cancer cells induce adipocytes to release FFA via activation of lipolysis (increased expression of ATGL and HSL) and inhibition of adipogenesis (through decreased expression of peroxisome proliferator-activated receptor-γ) (6,8). Adipocytederived FFAs favor the proliferative nature of breast tumor cells in the tumor microenvironment (8), by serving as available metabolic substrates for energy production via β-oxidation or storage in the form of lipid droplets for later utilization.…”

“…Obesity is identified as a casual factor in both the development as well as the progression of breast carcinogenesis (3,4), and is characterized by rapid adipose tissue remodeling (hypertrophy and hyperplasia) (5), increased synthesis of several adipokines such as leptin, resistin, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, macrophage chemoattractant protein-1 (MCP-1), and immune cell infiltration, all of which lead to a state of sustained low-grade inflammation. Mammary adipose tissue serves as a exogenous source of energy metabolites which favors the proliferation demand of breast cells in the tumor microenvironment (6,7). On the other hand, breast cancer cells can also modulate lipid metabolism by altering both de novo fatty acid (FA) synthesis as well as the catabolic break down of triacylglycerol's (TAGs) a process known as lipolysis.…”

“…On the other hand, breast cancer cells can also modulate lipid metabolism by altering both de novo fatty acid (FA) synthesis as well as the catabolic break down of triacylglycerol's (TAGs) a process known as lipolysis. This subsequently results in the release of free fatty acids (FFAs) which become available metabolic substrates for the benefit of breast cancer cell survival, either by storage in the form of lipid droplets, membrane lipids or energy production via β-oxidation supplying energy to these proliferating breast cancer cells (6,8).…”