Figure 2.

Role of fibroblasts in mammary gland branching and BC growth. Mammary branching morphogenesis and BC growth share many cellular processes, including epithelial cell proliferation, migration, invasion, and extracellular matrix (ECM) remodeling. These similarities explain why many morphogenic processes induced by fibroblasts are exploited intensively also in BC. (A) In normal conditions, fibroblasts guide mammary epithelial branching through paracrine signals that are mediated by growth factors, such as insulin-like growth factor (IGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF)2, and FGF9, low concentrations of transforming growth factor (TGF)-β and tightly regulated activation of the epithelial growth factor receptor (EGFR) signaling pathway. The expression of Sprouty/Spred family members in stromal cells plays a very important role during mammary branching. These morphogenic processes activated by fibroblasts are tightly controlled to ensure normal mammary gland development. (B) However, they become dysregulated and subverted during BC. In fact, BCAFs support BC growth by increasing extensively the same morphogenic pathways required for normal gland development. BCAFs massively upregulate the platelet derived growth factor receptor (PDGFR)α and EGFR signaling pathways, and produce higher levels of FGFs, HGF, and TGF-β than normal fibroblasts. The loss of Spry genes promotes, in fibroblasts, a cancer-associated fibroblast (CAF)-like phenotype and thus leads to BC growth.