A hypothetical model of paracrine versus autocrine signaling in mammary epithelial cells. Normal mammary epithelial cells expressing estrogen receptor (ER)α and progesterone receptor (PR) are restrained from proliferating, mediated by the growth-inhibitory actions of transforming growth factor (TGF)-β signaling, active in this population. The steroid receptor-positive cells secrete local-acting growth factors to induce neighboring cells to divide in a paracrine fashion. In early breast cancer progression, this normal paracrine mechanism may switch to an autocrine loop, allowing steroid receptor-positive cells to proliferate, possibly through the downregulation of active TGF-β signaling, leading to an upregulation of cell-cycle molecules such as cdc25A, cyclin E and cyclin-dependent kinase (cdk)2. IGF, insulin-like growth factor.