Energy transfer from adipocytes to cancer cells in breast cancer

Abstract

Limitations of the current therapeutic approach have raised the need for a novel therapeutic agent in breast cancer. Recently, interest in drugs targeting the tumor microenvironment (TME) had drawn attention in the treatment of breast cancer. Furthermore, recent studies have suggested the role of adipocytes, which are part of the TME, in tumor initiation, growth, and metastasis. In this study, we investigated the metabolic interaction between adipocytes and breast cancer cells and its potential as a new therapeutic target in breast cancer. Breast cancer cell lines and human breast cancer tissue samples were evaluated. Compared to cancer cells cultured alone, or the control group, those co-cultured with adipocytes showed lipid transfer from adipocytes to cancer cells and it was different according to the molecular subtype of breast cancer. Breast cancer cells affected the lipolysis of adipocytes and adipocytes affected the β-oxidation of breast cancer cells. The key molecule of the process was fatty acid binding protein 4 (FABP4), which is combined with free fatty acid (FFA) and supports its migration to cancer cells. When FABP4 was suppressed, lipid transfer between adipocytes and cancer cells, lipolysis of adipocytes, and β-oxidation of breast cancer cells were reduced. Furthermore, the expression of lipid metabolism-related proteins and lipolysis-related proteins in breast cancer with adipose stroma showed significantly different expression according to the region of breast cancer tissue. Taken together, we demonstrated the metabolic interaction between adipocytes and breast cancer cells. Breast cancer cells increase the lipolysis in adipocytes and produce a fatty acid, and fatty acid enters into cancer cells. Also, adipocytes contribute to the survival and growth of cancer cells through increased mitochondrial β-oxidation by using fatty acid from adipocytes. The key molecule of the process is FABP4 and when FABP4 is suppressed, the metabolic interaction is reduced, suggesting its role as a potential therapeutic target.

The pleiotropic roles of adipocyte secretome in remodeling breast cancer

“…Byon et al proved that FFAs could enhance PAI-1 expression in MDA-MB-231 cells and facilitate breast cancer progression in vitro, by partially inducing SMAD4 [ 106 ]. breast cancer cells affect lipolysis in adipocytes, and adipocytes affect β-oxidation in breast cancer cells [ 107 ]. Concretely, Adipocytes promoted breast cancer growth through mitochondrial β-oxidation by using fatty acid from adipocytes, of which process fatty-acid-binding protein 4 (FABP4) was a key activated target for metabolic interaction.…”

Stromal Co-Cultivation for Modeling Breast Cancer Dormancy in the Bone Marrow

“…BC cells and adipocytes have reciprocal metabolic effects on each other. Human BC cell lines in transwell inserts can induce an increased lipolysis in co-cultivated adipocytes differentiated from 3T3-L1 cells [ 131 ]. In turn, the adipocytes transfer newly produced free fatty acids (FFAs) to the BC cells [ 131 ].…”

Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

“…The adipokines plasminogen activator inhibitor 1 (PAI-1), FABP4, and secreted frizzled-related protein 5 (SFRP5) are also found in the local environment of the breast and have been shown to contribute to breast cancer progression [ 64 , 193 , 194 , 195 , 196 , 197 , 198 , 199 ]. Higher levels of the adipokine, PAI-1, in breast cancer were found to correlate with poor prognosis in breast cancer patients [ 193 ].…”

“…Focusing on the mechanisms in breast cancer progression, FABP4 enhances proliferation in both MCF-7 cells (ER-positive) and MDA-MB-231 TNBC cells but does not appear to affect the migration potential [ 197 ]. FABP4 is involved in the lipid metabolism in the tumor microenvironment, and suppression of FABP4 reduces the lipid transfer between adipocytes and cancer cells, which could explain the observed proliferative response in the above-mentioned study [ 198 ]. Secreted SFRP5 is a fairly novel adipokine in the research area regarding the association between obesity and breast cancer, as reviewed by Zhao et al [ 53 ].…”

“…Suppression of FABP4 reduces the lipid transfer between adipocytes and cancer cells. [197,198] SFRP5 Decreased A high level of SFRP5 in the tumor tissue is associated with better outcomes. [199] Abbreviations: ER = estrogen receptor; MMP = matrix metalloproteinase; TNBC = triple-negative breast cancer; VEGF = vascular endothelial growth factor; EMT = epithelial-mesenchymal transition; TNF-α = tumor necrosis factor alpha; IL = interleukin; PD-1 = programmed cell death 1; CAP1 = adenylyl cyclase-associated protein-1; PAI-1 = plasminogen activator inhibitor 1; FABP4 = fatty acid-binding protein 4; SFRP5 = secreted frizzled-related protein 5.…”