Figure 3

Diagrams depicting stromal-epithelial signaling affecting mammary ductal growth and its inhibition. (a) Growth stimulatory signals. Endocrine mammogens [estrogen (E), growth hormone (GH)], acting on stromal targets in front of the end bud, stimulate the synthesis of the local mammogens epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and members of the activin/inhibin family. From the end bud, unknown retrograde signals (broken lines) stimulate vicinal DNA synthesis and attract macrophages and eosinophils. The stimulation of lateral branches along mature ducts involves the focal loss or inactivation of transforming growth factor-β₁ (TGF-β1), relieving the inhibition of hepatocyte growth factor (HGF) synthesis and permitting lateral branch development. Outer shaded zone, fibrous sheath; L, lumen. (b) TGF-β in growth inhibition and induction of the periductal fibrous sheath. Although end buds are inhibited by exogenous TGF-β, it remains unproven as the natural mechanism for end bud growth termination. In a purely speculative model for fibrous induction, TGF-β, acting in a paracrine mode on cap/myoepithelial cells (black layer), induces parathyroid-hormone-related protein (P). Secreted parathyroid-hormone-related protein then acts on stromal targets, inducing highly localized fibrosis. Finally, along the duct, TGF-β₁ inhibits lateral branching by blocking HGF action.