The specific roles of adipose tissue in breast cancer

Breast cancer has surpassed lung cancer to become the most prevalent malignancy worldwide, characterized by high heterogeneity and complex pathological mechanisms. Epidemiological evidence firmly establishes obesity as a significant risk factor for breast cancer, particularly in postmenopausal women, correlating with poor prognosis and increased metastasis. Adipose tissue, far from being merely an energy storage depot, is recognized as the body′s largest endocrine organ. While adipose tissue contributes to the progression of various cancers including hepatic, colorectal, and pancreatic cancers through shared mechanisms such as chronic inflammation and metabolic dysregulation, the breast presents a unique anatomical landscape where epithelial cells are deeply embedded within a fat-rich stroma. This review aims to synthesize the general mechanisms by which adipose tissue promotes tumorigenesis and, more importantly, to dissect the specific, intimate crosstalk between breast cancer cells and the surrounding adipose microenvironment, highlighting the distinct roles of cancer-associated adipocytes (CAAs) and local estrogen biosynthesis. Adipose tissue exerts a pro-tumorigenic influence across multiple cancer types through systemic low-grade chronic inflammation, insulin/IGF-1 signaling dysregulation, and altered adipokine secretion (e.g., increased leptin and decreased adiponectin). However, adipose-tumor crosstalk in breast cancer is uniquely direct and sustained. Specifically, breast cancer cells induce adjacent mature adipocytes to undergo de-differentiation into CAAs. This process, regulated by factors such as Wnt, TGF-β, and adrenomedullin (AM), transforms adipocytes into fibroblast-like cells with reduced lipid droplets and activated pro-inflammatory phenotypes. CAAs undergo metabolic reprogramming, accelerating lipolysis via ATGL and HSL activation to release free fatty acids (FFAs). These FFAs are taken up by cancer cells for β-oxidation, fueling rapid proliferation and membrane synthesis. Furthermore, CAAs secrete a myriad of cytokines (e.g., IL-6, CCL2), which not only activate STAT3 and ERK1/2 pathways to enhance tumor invasiveness but also recruit immune cells, notably promoting the polarization of macrophages towards the immunosuppressive M2 phenotype. A defining feature of the breast cancer-adipose nexus, particularly in ER-positive postmenopausal cases, is the profound upregulation of local estrogen synthesis. Adipose tissue serves as the primary source of estrogen via the aromatase enzyme (CYP19A1). This process is amplified by intricate positive feedback loops within the tumor microenvironment: obesity-induced inflammation elevates PGE2 and TNF-α, while tumor-derived oncostatin M (OSM) activates the JAK/STAT3 pathway in adipocytes. These signals converge to upregulate CYP19A1 expression, resulting in significantly higher level of local estrogen than circulating system, thereby driving hormone-dependent tumor growth. Current clinical translation efforts, including microphysiological systems (MPS) and 3D bioprinting, are improving our ability to model these interactions, while radiomic tools like MRI proton density fat fraction (PDFF) offer non-invasive risk assessment. Despite these advances, the causal hierarchy and dynamic regulation of the adipose-tumor dialogue remain to be fully elucidated. Future research must leverage single-cell multi-omics and spatial transcriptomics to map the heterogeneity of the tumor-adipose interface and clarify the metabolic fate of adipocyte-derived lipids. Ultimately, targeting the specific signaling axes of CAAs, such as the blockage of pro-inflammatory cytokines or the inhibition of specific metabolic enzymes, without disrupting systemic metabolic homeostasis, represents a promising frontier for developing novel, personalized therapeutic strategies for breast cancer.