Metabolic vulnerability is a target of the antineoplastic effect of breastfeeding.

Lactation is associated with a protective effect against breast and ovarian cancer as well as against cardiovascular diseases suggesting a systemic effect. Here, we show that the serum of lactating mice and breastfeeding mothers have targeted antineoplastic effects, while serum from virgin mice and matched post-partum but non-lactating women do not. The effect is specific to cancer cells expressing Pappalysin-A (PAPP-A), a target that is shared among diseases affected by breastfeeding. RNAseq revealed that lactating serum inhibits mitochondrial function and we found that PAPP-A alone lowers mitochondrial function, suggesting that lactation serum acts by exploiting the metabolic vulnerability of these cancer cells. Using serum proteomics, we identified corticotropin release factor (CRF) as being unique to serum of lactating women and we show that CRF alone mimics the mitochondrial and anti-tumorigenic effect of lactating serum. Blocking the CRF receptor, inhibits the protective effect of lactating serum. Since CRF has shown efficacy in the clinic in other settings, our findings raise the possibility to extend its use to mimic or enhance the protective effect of breastfeeding. SummaryWe show that the serum from lactating women has anti-cancer activity and used multi-omics approaches to identify corticotropin release factor as a peptide able to mimic the effect of lactating serum by targeting cells with low mitochondrial activity.