Cabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in Brca1-Mutant Mice and Reduces Risk in Younger Women

Breast cancer that arises in the postpartum period often carries a poor prognosis. The increasing trend of later-life pregnancies further exacerbates this risk. We urgently need chemoprevention strategies that reduce risk for postpartum period tumors, especially for more-aggressive ER-negative tumors and for those that arise in women with a genetic susceptibility. Here, we report that a single post-lactation dose of cabergoline, a dopaminergic agonist that blocks prolactin secretion, delays the onset and reduces the incidence of mammary cancer that arises postpartum in K14-Cre; Brca1 ^F/F , Trp53 ^F/F mice. In these mice, cabergoline treatment remodels the postpartum mammary gland by potentiating involution, reducing ductal area and proliferation, and reversing T cell exhaustion, potentially through modulation of ion channel expression. Notably, independent retrospective studies in two large cohorts of European women demonstrated a markedly lower incidence of postpartum breast cancer in those treated with cabergoline compared to a control group, with a meta-analysis indicating an approximate 69% reduction in risk. Our work underscores the importance of targeting post-lactational involution as a strategy for the prevention of postpartum breast cancer and identifies cabergoline as a novel, low-risk chemoprevention strategy during the vulnerable postpartum window by promoting physiological remodeling and mitigating immune dysfunction.