Role of adipose tissue in breast cancer progression: prognostic biomarkers

Background Obesity (Ob) is a metabolic disease, considered a globally healthy problem, associated with a heightened risk of tumor development and progression, including breast cancer (BC). In the presence of abundant adipose tissue (AT), the breast gland undergoes multiple changes, mediated by chronic inflammation and oxidative stress, which favor the dynamic crosstalk between cancer and tumor microenvironment (TME) cells in BC progression. Compelling evidence demonstrates that a subpopulation of neoplastic cells, named cancer stem cells (CSCs), promotes recurrence, relapse, metastatic spread, and anti-cancer drug resistance. It has been pointed out that CSCs benefit from: i) the presence of a pro-inflammatory microenvironment; ii) induction of DNA damage and repair mechanisms; iii) immune cells recruitment, including macrophages; iv) metabolism rewiring and v) aberrant survival pathways' activation.Aims1. Dissecting the dynamic interplay between breast cancer sphere cells (BCSphCs) and adipose stem cells (ASCs).2. Explore the pro-inflammatory role of AT in the recruitment of macrophages in BC.3. Define the contribution of TME in the induction of DNA damage in BC.ResultsTaking advantage of our collection of BCSphCs and ASCs isolated from obese (ASCs/Ob) and normal weight (ASCs/NW) BC patients, we analyzed the molecular mechanisms, boosted by AT, mediating tumor growth and progression. We first characterized the difference between ASCs/NW and ASCs/Ob. Although the two ASC populations display similar mesenchymal stem-cell features, ASCs isolated from obese BC patients showed an increased production of pro-inflammatory and pro-tumorigenic cytokines. Moreover, ASCs/Ob enhanced the proliferative and the tumorigenic potential of BCSphCs, as well as reprogrammed stemness- and epithelial to mesenchymal transition (EMT)-related gene expression and boosted the activation of chemotactic signals. ASCs/Ob-secreted cytokines promoted DNA damage in BCSphCs and primed the switch of infiltrating macrophages toward M2-like cells. Finally, we observed that in BC tissue derived from obese patients the inflammatory environment is mainly nourished by macrophages, expressing CD68 and CD163, which are mainly located close to BC cells positive for γH2AX.ConclusionHere, we observed that ASCs/Ob induce transcriptomic reprogramming in BCSphCs, establishing a permissive microenvironment and favoring M2-like macrophage recruitment and BC cell DNA damage accumulation. The obtained results could clarify the molecular mechanisms shaped by evolving TME during BC progression and lead to prognostic biomarker identification and the design of more effective therapeutic regimens for advanced BC treatment.