Harnessing Post-Lactational Involution for Breast Cancer Prevention
Manuel Jesús Pérez Baena
Centro de Investigación del Cáncer (CSIC-USAL-FICUS)
Postpartum breast cancer, especially triple-negative breast cancer (TNBC), is linked to poor prognosis and limited prevention options. This clinical challenge is particularly relevant during post-lactational mammary involution, a temporary physiological process involving epithelial cell removal and tissue remodeling that has been associated with a temporary increase in breast cancer risk. In this study, we investigated whether enhancing the normal involution process during this vulnerable period could provide long-term protection against tumor development. Using complementary experimental systems, including 3D mammary organoids and a Brca1/p53-deficient mouse model of TNBC, we assessed the effects of short interventions administered at the start of involution. These interventions accelerated key aspects of tissue regression during the acute phase, such as epithelial clearance and remodeling, and were linked to coordinated molecular changes indicative of a more complete post-lactational state. Notably, these early changes were followed by lasting modifications in the mammary gland, including a reduced epithelial compartment, lower cell proliferation, and stable molecular profiles associated with decreased tumor risk. Long-term studies showed that this remodeling led to delayed tumor onset and a lower incidence of TNBC. Overall, these findings highlight the post-lactational period as a promising window for breast cancer prevention and suggest that brief reinforcement of physiological involution could provide lasting protection in high-risk individuals.