Control of mammary gland development by estrogen and progesterone. Systemic hormones act on estrogen receptor (ER) alpha/progesterone receptor (PR)-positive sensor cells. During ductal elongation, estrogen (17β-estradiol) induces expression of amphiregulin (AREG) that is activated by the extracellular protease ADAM17. AREG acts via the epidermal growth factor receptor (EGFR) on stromal cells. In response to this stimulation, the stromal cells release factors such as fibroblast growth factors (FGFs) and insulin-like growth factor-1 (IGF-1) that signal back to the epithelium, inducing proliferation. Other proteins are also induced by estrogen (E), such as LCN2, SLP1 and HbP17, but their biological function remains to be elucidated. During adulthood, in the presence of estrogens, progesterone (P) induces side branching. In response to progesterone, the ER/PR-positive sensor cells release several paracrine factors such as Wnt4, receptor activator of NF-κB ligand (RANKL) and calcitonin (CT), which act on neighboring cells, inducing proliferation and stem cell expansion. Ad, adipocyte; BM, basal membrane; CTR, calcitonin receptor; Fb, fibroblast; IC, immune cell; LC, luminal cell; MC, myoepithelial cell; RANK, receptor activator of NF-κB; TGF, transforming growth factor.