Exogenous Fatty Acids Modulate ER Lipid Composition and Metabolism in Breast Cancer Cells

Abstract

(1) Background: Lipid metabolism is a fundamental hallmark of all tumors, especially of breast cancer. Few studies describe the different lipid metabolisms and sensitivities to the microenvironment of breast cancer cell subtypes that influence the proliferation, aggressiveness, and success of therapy. This study describes the impact of lipid microenvironment on endoplasmic reticulum (ER) membrane and metabolic activity in two breast cancer cell lines with Luminal A and triple-negative breast cancer (TNBC) features. (2) Methods: We investigated the peculiar lipid phenotype of a TNBC cell line, MDA-MB-231, and a Luminal A cell line, MCF7, and their different sensitivity to exogenous fatty acids (i.e., palmitic acid (PA) and docosahexaenoic acid (DHA)). Moreover, we verified the impact of exogenous fatty acids on ER lipid composition. (3) Results: The data obtained demonstrate that MDA-MB-231 cells are more sensitive to the lipid microenvironment and that both PA and DHA are able to remodel their ER membranes with consequences on resident enzyme activity. On the contrary, MCF7 cells are less sensitive to PA, whereas they incorporate DHA, although less efficiently than MDA-MB-231 cells. (4) Conclusions: This study sustains the importance of lipid metabolism as an innovative hallmark to discriminate breast cancer subclasses and to develop personalized and innovative pharmacological strategies. The different sensitivities to the lipid environment shown by MCF7 and MDA-MB-231 cells might be related to cell malignancy and chemoresistance onset. In the future, this new approach could lead to a substantial decrease both in deleterious side effects for the patients and in the cost of entire therapeutic treatments coupled with increased therapy efficiency.

Adipose Tissue—Breast Cancer Crosstalk Leads to Increased Tumor Lipogenesis Associated with Enhanced Tumor Growth

“…As for breast cancer progression specifically, several studies show that fatty acid synthase (FASN) inhibition decreases proliferation and increases the chemosensitivity of many breast cancer cell lines as well as in experimental breast cancer models [22][23][24][25][26][27]. However, breast cancers are heterogenous with respect to fatty acid sensitivity [28] and metabolism, and, based on gene expression data, the less aggressive luminal A ER-positive breast cancer subtypes appear to rely on a balance between de novo lipogenesis and fatty acid oxidation as sources for both biomass and energy requirements, while basal-like, triple-negative subtypes may, to a larger extent, use exogenous fatty acids [29].…”

A novel automated image analysis pipeline for quantifying morphological changes to the endoplasmic reticulum in cultured human cells

“…Likewise, here we report that treatment with thapsigargin or tunicamycin does not significantly alter tubular SER polygon area or the proportion of dense RER within U-2 OS cells. Lipid availability has been linked to ER morphology [25] and treatment with the saturated free fatty acid palmitate induces ER expansion and stress in several cell types [32,[60][61][62][63]. Here we show that treatment with a low concentration of palmitic acid increases the area of SER polygons.…”

MammaPrint and BluePrint comprehensively capture the cancer hallmarks in early‐stage breast cancer patients

“… 59 Moreover, a recent study showed that luminal A and TNBC cell lines have different lipid phenotypes, suggesting that different lipid metabolism might discriminate breast cancer subclasses. 60 This might explain the discriminative feature of ACBD4 as a luminal associated gene in the BP gene signature.…”