Organellar responses to lactation-induced stress impact the fate of post-partum mammary glands.

Breastfeeding protects against breast cancer, but not in all women and the mechanism remains elusive. Lactation implicates secretion of proteins through the endoplasmic reticulum (ER) and ER- mitochondria contacts for lipid metabolism. We show that in mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB) the outcome of lactation differs drastically. We analyzed the unfolded protein responses (UPR) of both organelles during lactation. In contrast to the BL/6C57mice, in BL/6NZB females, UPRs signaling is abruptly inhibited, no apoptosis is observed, post-partum hyperplasia develops and RNAseq demonstrates expression of pro-tumorigenic genes, which is consistent with increased post-partum tumor development. However, forced-induction of pro-apoptotic UPRER reverses this phenotype. Remarkably, milk fatty acids (FA) differ between genotypes and correlate with breast cancer risk in humans. These results indicate that mitochondrial genetics modulates organellar responses to lactation and its protective effect. Our results further raise the possibility of using milk FA-signature as a read-out of the underlying biology to predict risk of breast cancer in the future.