Abstract
The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy controls breast development and modifies breast cancer risk. How these hormones uniquely impact each cell type in the breast is not well understood, because many of their effects are indirect--only a fraction of cells express hormone receptors. Here, we use single-cell transcriptional analysis to reconstruct in silico trajectories of the response to cycling hormones in the human breast. We find that during the menstrual cycle, rising estrogen and progesterone levels drive two distinct paracrine signaling states in hormone-responsive cells. These paracrine signals trigger a cascade of secondary responses in other cell types, including an "involution" transcriptional signature, extracellular matrix remodeling, angiogenesis, and a switch between a pro- and anti-inflammatory immune microenvironment. We observe similar cell state changes in women using hormonal contraceptives. We additionally find that history of prior pregnancy alters epithelial composition, increasing the proportion of myoepithelial cells and decreasing the proportion of hormone-responsive cells. These results provide systems-level insight into the links between hormone cycling and breast cancer risk.
