AbstractIn rodents, weaning-induced mammary gland involution supports increased mammary tumor incidence, growth, and progression to metastasis. Further, the protumor attributes of gland involution are COX-2 dependent and mitigated by short-duration non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a potential prevention strategy. However, the transition from lactation to postweaning breast involution has not been rigorously evaluated in healthy women. Here we queried breast biopsies from healthy women (n = 112) obtained at nulliparity, lactation, and multiple postweaning time points using quantitative immunohistochemistry. We found that mammary remodeling programs observed in rodents are mirrored in the human breast. Specifically, lactation associates with the expansion of large, secretory mammary lobules and weaning associates with lobule loss concurrent with epithelial cell death and stromal hallmarks of wound healing, including COX-2 upregulation. Altogether, our data demonstrate that weaning-induced breast involution occurs rapidly, concurrent with protumor-like attributes, and is a potential target for NSAID-based breast cancer prevention.