The role of adipocytes in the breast cancer tumour microenvironment

Breast cancer is the commonest female malignancy worldwide. Although 10-year survival is good at over 75%, patients with more advanced or aggressive cancers have markedly poorer outcomes. Over recent years, the (benign) tissue local to a malignancy has generated considerable interest as promoting cancer progression. Within this tumour microenvironment, the role of the once neglected adipocyte is becoming clearer, although much work is still needed to fully understand the part it plays. This study aimed to further investigate the role of adipocytes in the breast cancer tumour microenvironment, with a view to identifying cytokines which may, with further research, be potential novel therapeutic targets and improve breast cancer outcome. First, experiments were conducted to analyse the effects on breast cancer cell line proliferation when co-cultured with (SGBS) adipocytes. ER+ (MCF-7) and triple negative (MDA-MB-231) cell lines were selected. Experiments demonstrated an increase in MCF-7 proliferation when co-cultured with both pre-differentiated and mature SGBS cells. Rate of proliferation of MDA-MB-231 cells was decreased when co-cultured with pre-differentiated SGBS cells but increased when grown alongside mature adipocytes. Next, proteome profile analysis was undertaken to investigate cytokine secretion of fresh human breast tissue explants from patients with ER+ and triple negative cancers. Peri-tumoural and distant adipose tissue was cultured. Cytokines in peri-tumoural ER+ explant media were reduced as compared to the resection margin (control) media, whereas a greater number of cytokines were increased in triple negative peri-tumoural media. Additionally, further SGBS/MCF-7 co-cultures were undertaken, and proteome analysis conducted. Interestingly, this demonstrated an increase in a greater number of cytokines in the media of SGBS cells co-cultured as compared to media from peri-tumoural (ER+) explant tissue. Gene expression analysis was undertaken for select cytokines and CHI3L1 identified as a cytokine of interest. Finally, MCF-7 and MDA-MB-231 cells were cultured in media containing CHI3L1, and proliferation assessed. MCF-7 proliferation was significantly higher in stimulated cells, and MDA-MB-231 cells demonstrated some increase in proliferation also. CHI3L1 has thus been identified as a potential novel therapeutic target. More research is needed to further explore its stimulatory effects on breast cancer cells