Metabolic vulnerability is a target of the antineoplastic effect of breastfeeding

Lactation is associated with a protective effect against breast and ovarian cancer, but the mechanism is unknown. Pappalysin-A (PAPP-A) is an extracellular protease normally expressed on the surface of placental trophoblasts during pregnancy but can also acts as an oncogene. We show that the serum of lactating mice or breastfeeding mothers protects against PAPP-A+ cancers specifically, while serum from virgin mice or parity-matched but non-lactating women do not. RNAseq revealed that lactating serum targets mitochondrial function in PAPP-A+ cancer cells leading to senescence. Further, we found that overexpression of PAPP-A in cancer cells is associated with lower mitochondrial function. These observations suggest that the anti-tumorigenic effect of lactation serum acts by exploiting the metabolic vulnerability of PAPP-A+ cancer cells. We identified corticotropin release hormone (CRH) using serum proteomics and show that CRF, the synthetic form of CRH, alone mimics the effect of lactating serum. Our study therefore identifies a mechanism of the protective effect of lactation against cancers and raises the possibility to use CRF as a therapeutic approach to mimic or enhance the protective effect of lactation for the prevention of breast cancer.