Dynamics, function, and regulation of mammary stem cells in development and disease

Understanding the heterogeneity of mammary epithelial cells and their contributions to postnatal development and regeneration is of great importance. Recent advances have defined the intrinsic complexity of the mammary epithelium, its stromal interactions, and the ontogeny of adult stem and progenitor cells. These insights have not only refined our understanding of normal mammary gland biology but also highlighted how specific epithelial subsets serve as cells of origin and targets of transformation in breast cancer. The close parallels between mammary stem cells and tumor-initiating cells, particularly their shared plasticity and self-renewal, highlight stemness as a central node linking developmental programs to malignant transformation. Both populations are shaped by microenvironmental cues and specialized niche components that regulate their maintenance, fate, and susceptibility to oncogenic reprogramming. Here, we review recent advances in mammary epithelial biology, emphasizing the key signaling pathways and stromal interactions that govern mammary stem cell behavior during development and tumorigenesis. We further discuss how developmental programs and microenvironmental cues that sustain mammary morphogenesis are subverted during cancer progression, with particular attention to pregnancy-associated transient susceptibility and aging-associated cancer risk. Overall, this Review offers a framework for understanding how normal mammary epithelial programs are redirected during malignant progression.