Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences

Abstract

Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions.

Keywords: adipocyte dedifferentiation; adipogenesis; breast cancer; cancer-associated adipocytes (CAA); signaling.

Figure 1

Transcriptional regulators of adipogenesis. Multipotent mesenchymal stem cells (MSC) upon adipogenic stimuli give rise to preadipocytes that, after clonal expansion and subsequent differentiation, become mature adipocytes. Molecules relevant in this process are shown with their approximate induction and duration reflected by lines. The preadipocyte factor 1 (Pref-1) is expressed in preadipocytes and participates in the maintenance of this state. It is an inhibitor of adipogenesis and its expression must be reduced during adipocyte differentiation. CCAAT-enhancer-binding protein C/EBPβ is involved in adipogenesis at an early phase and, together with C/EBPδ, regulates the transcription of the peroxisome proliferator-activated receptor γ (PPARγ). PPARγ with C/EBPα cooperatively induces adipocyte differentiation, regulating the expression of adipocyte-specific genes.

Figure 2

Extracellular regulators of adipogenesis. Signals from activators and repressors of adipogenesis are integrated in the nucleus by transcription factors that directly or indirectly activate (red arrows) or inhibit (blue lines) the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα). The induction of PPARγ by p38 is related to the BMP2 pathway, and the red arrow from ERK is related to insulin and FGF pathways. AKT, protein kinase B; BMP, bone morphogenetic protein; CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth-factor receptor; FOXO, forkhead protein; FZD, frizzled family receptors; GATA, GATA binding protein; GC, glucocorticoids; GCR, GC receptor; Gli, GLI family zinc finger; IL, interleukin; IR, insulin receptor; JAK, Janus kinase; JNK, Jun n-terminal kinase; MEK, mitogen-activated MAPK/ERK kinase; mTOR, mammalian target of rapamycin; N1ICD, Notch1 intracellular domain; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; Notch1; Notch homolog 1, translocation-associated; p38, protein 38 MAPK; PI3K, phosphatidylinositol-3 kinase; PTC, patched; SHN2, schnurri-2; SHH, sonic hedgehog; SMAD, SMAD family member; STAT, signal transducer and activator of transcription; TCF7, T-cell factor 7; TNF, tumor necrosis factor; TNFR, TNF receptor; TGFβ, transforming-growth factor β; WNT, wingless-related integration site.

Figure 3

Signaling regulation of adipocyte dedifferentiation. Pathways described to be involved in adipocyte dedifferentiation in cancer and in other pathologies like fibrosis and liposarcoma. ?, indicates that the molecule(s) contained in exosomes and involved in inducing the adipocyte pro-inflammatory phenotype are unknown and have only pro-inflammatory effects (^#); *, IL-6 was described to induce lipolysis and, thus, to reduce triglyceride (TG) content, while adrenomedullin (ADM) was described to induce the phosphorylation of hormone-sensitive lipase (HSL), a step necessary for lipolysis induction that reduces the TG content; ^, miRs were demonstrated to induce PPARγ reduction. Blue and red arrows indicate reduction and increase, respectively. miR, microRNA; FA, fatty acid; pHSL, phosphorylated hormone sensitive lipase; TGF, transforming growth factor; N1ICD, Notch1 intracellular domain; WNT, wingless-related integration site.

Figure 4

Pro-tumoral factors released by cancer-associated adipocytes (CAAs). CAAs release free or exosome-associated molecules that directly or indirectly, through the modulation of the immune cells, induce the acquisition of aggressive features in breast cancer (BC) cells. The blue and red arrows indicate the increased and decreased release compared to mature adipocytes. In the central panel, blue lines indicate that cells are blocked in their function; red arrows indicate that cells are recruited/activated. BHB, β-hydroxybutyrate; DC, dendritic cells; FFAs, free fatty acids; IL, interleukin; HGF, hepatocyte growth factor; IGF, insulin growth factor; IGFBP2, IGF binding protein 2; M, macrophages; MDSC, myeloid derived suppressor cells; NK, natural killer cells; PAI-1, plasminogen activator inhibitor 1; PLOD2, procollagen-lysine 2-oxoglutarate 5-dioxygenase 2; TGFβ, transforming growth factor β; TAN, tumor associated neutrophils; TNF, tumor necrosis factor; T Reg, regulatory T cells; VEGF, vascular endothelial growth factor.