Breast-Associated Adipocytes Secretome Induce Fatty Acid Uptake and Invasiveness in Breast Cancer Cells via CD36 Independently of Body Mass Index, Menopausal Status and Mammary Density.

Maurice Zaoui,Mehdi Morel,Michèle Sabbah,Véronique Béréziat,Soraya Fellahi,Nathalie Ferrand,Annette Kragh Larsen,Antonin Lamazière,Jean-Philippe Bastard,Michael Atlan

doi:10.3390/cancers11122012

Abstract

Breast adiposity is correlated with body mass index, menopausal status and mammary density. We here wish to establish how these factors influence the cross-talk between breast adipocytes and normal or malignant breast cells. Adipocyte-derived stem cells (ASCs) were obtained from healthy women and classified into six distinct groups based on body mass index, menopausal status and mammary density. The ASCs were induced to differentiate, and the influence of their conditioned media (ACM) was determined. Unexpectedly, there were no detectable differences in adipogenic differentiation and secretion between the six ASC groups, while their corresponding ACMs had no detectable influence on normal breast cells. In clear contrast, all ACMs profoundly influenced the proliferation, migration and invasiveness of malignant breast cells and increased the number of lipid droplets in their cytoplasm via increased expression of the fatty acid receptor CD36, thereby increasing fatty acid uptake. Importantly, inhibition of CD36 reduced lipid droplet accumulation and attenuated the migration and invasion of the breast cancer cells. These findings suggest that breast-associated adipocytes potentiate the invasiveness of breast cancer cells which, at least in part, is mediated by metabolic reprogramming via CD36-mediated fatty acid uptake.

Highlights

Breast cancer remains the leading cause of cancer death in women and is increasing worldwide [1].The increased incidence is not a result of aging, since it is observed for all age groups, suggesting that other risk factors should be considered
Results are presented as means ± standard of 19 error of the mean (SEM). (B) Whole cell lysates were extracted at day 0 and 14 of4ASCs differentiation and were subjected to immunoblotting with anti-PPARγ and anti-FABP4 antibodies
These results show that normal breast cells and invasion of tumor cells, we focused on adipocyte conditioned media (ACM) derived from non-obese premenopausal or obese are not able to invade under any conditions, while the ACM has a limited effect on the migration and migratory and invasive capacities in the presence of all types of ACM

Summary

Introduction

Breast cancer remains the leading cause of cancer death in women and is increasing worldwide [1].The increased incidence is not a result of aging, since it is observed for all age groups, suggesting that other risk factors should be considered. Obesity induces inflammation of the adipose tissue, which will induce an inflammatory state leading to insulin resistance [6,7] This inflammatory state leads to elevated levels of circulating leptin and proinflammatory cytokines—factors that have previously been implicated in breast cancer progression [8,9,10]. Since AT becomes an important source of estrogen due to the high local expression of aromatase in postmenopausal women [12], obesity increases the risk of postmenopausal women developing hormone receptor-positive breast cancers [13,14,15]. Recent studies of premenopausal women provide evidence for a relationship between overweight/obesity and an increased risk of triple negative breast cancer, but a lower risk for hormone receptor-positive breast cancer [15,16,17]

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