Using mortal non-tumorigenic human mammary epithelial cells and fibroblasts, Fordyce and colleagues show that an epithelial stress response promotes pro-tumorigenic changes in mammary fibroblasts. Fibroblast reprogramming was dependent on activin A or prostaglandin E2 produced by epithelial cells and, in turn, promoted enhanced migration of epithelial cells. These events in epithelial cells in vitro, including telomere loss, heightened DNA damage response, and activin A expression, are observed in breast ductal carcinoma in situ lesions surrounded by stroma bearing hallmarks of activated fibroblasts and immune and endothelial cell infiltration. Thus, reciprocal epithelial-stromal interactions facilitate progression to malignancy and occur even at the earliest stages of mammary tumorigenesis.