Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration

Seher Balaban,Lisa S Lee,Robert F Shearer,Daniel J Fazakerley,Harrison C Shtein,Kristen C Thomas,Darren N Saunders,Andrew J Hoy,Michelle Van Geldermalsen,Rose Cairns,Thomas Grewal,Jeff Holst,Mark Schreuder

doi:10.1186/s40170-016-0163-7

Abstract

BackgroundObesity is associated with increased recurrence and reduced survival of breast cancer. Adipocytes constitute a significant component of breast tissue, yet their role in provisioning metabolic substrates to support breast cancer progression is poorly understood.ResultsHere, we show that co-culture of breast cancer cells with adipocytes revealed cancer cell-stimulated depletion of adipocyte triacylglycerol. Adipocyte-derived free fatty acids were transferred to breast cancer cells, driving fatty acid metabolism via increased CPT1A and electron transport chain complex protein levels, resulting in increased proliferation and migration. Notably, fatty acid transfer to breast cancer cells was enhanced from “obese” adipocytes, concomitant with increased stimulation of cancer cell proliferation and migration. This adipocyte-stimulated breast cancer cell proliferation was dependent on lipolytic processes since HSL/ATGL knockdown attenuated cancer cell responses.ConclusionsThese findings highlight a novel and potentially important role for adipocyte lipolysis in the provision of metabolic substrates to breast cancer cells, thereby supporting cancer progression.

Highlights

Obesity is associated with increased recurrence and reduced survival of breast cancer
Breast cancer cells stimulate lipolysis in mature 3T3-L1 adipocytes and accumulate adipocyte-derived fatty acids A number of studies have described reciprocal crosstalk between cancer cells and stromal adipocytes, but these have largely focused on endocrine and paracrine signaling mechanisms
We observed an accompanying reduction in adipocyte TAG content following co-culture with breast cancer cells (Fig. 1d). These data demonstrate that breast cancer cells stimulate fatty acid mobilization from adipocyte TAG stores, consistent with previous studies [9, 34, 35]

Summary

Introduction

Obesity is associated with increased recurrence and reduced survival of breast cancer. Martinez-Outschoorn and colleagues [7] have proposed a two-compartment energy model to Balaban et al Cancer & Metabolism (2017) 5:1 describe the metabolic role of tumor stroma in cancer progression In this model, tumors act as metabolic parasites, sequestering metabolic substrates including lactate, glutamine, and fatty acids from local/stromal sources via stimulation of catabolic pathways such as autophagy, glycolysis, and lipolysis. Tumors act as metabolic parasites, sequestering metabolic substrates including lactate, glutamine, and fatty acids from local/stromal sources via stimulation of catabolic pathways such as autophagy, glycolysis, and lipolysis This is likely to be highly relevant in the breast where adipocytes, professional lipid storage cells, are the predominant cell population and are capable of secreting significant quantities of metabolic substrates such as glycerol and fatty acids. Little attention has been paid to the significant potential for stromal adipocytes to provide metabolic substrates, thereby supporting breast cancer progression

Methods

Results

Discussion

Conclusion