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

Angela Maria Rizzo,Gigliola Montorfano,Irma Colombo,Paola Antonia Corsetto,Stefania Zava

doi:10.3390/cells10010175

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.

Highlights

Cancer is a highly complicated disease because of its genetic and metabolic heterogeneity and complexity
The MCF7 cell line is characterized by positive estrogen receptor and/or progesterone receptor expression and exhibits a high level of luminal feature-correlated genes/proteins such as ERα or luminal keratins and transcription factors such as GATA3 and FOXA1
The MDA-MB-231 cell line is characterized by low or no expression of all three receptor markers and by high invasivity and aggressiveness; this line is classified as triple negative breast cancer (TNBC)

Summary

Introduction

Cancer is a highly complicated disease because of its genetic and metabolic heterogeneity and complexity. Distinct genetic alterations, oncogenic signaling, and epigenetic changes are responsible for tumorigenesis [1]. Metabolic alterations represent a hallmark of cancer controlling tumor progression and metastasis [2]. The most understood metabolic perturbation in cancer cells is the “Warburg effect”, an energetically wasteful alteration of glucose metabolism [3]. Protein, and amino acid metabolism in tumor cells has already been extensively dissected, lipid metabolism has only recently come to the attention of the scientific community. This field is still largely unexplored, great benefits could come from a deeper understanding of cancer cell lipid phenotype and the susceptibility to the lipid microenvironment

Methods

Results

Discussion

Conclusion