Idiosyncratic nature of lactation reveals link to breast cancer risk.
Breastfeeding protects against breast cancer in some women but not others, however the mechanism remains elusive. Lactation requires intense secretory activity of the endoplasmic reticulum (ER) for the production of milk proteins and ER- mitochondria contacts for lipid synthesis. We show that in female mice that share the same nuclear genome (BL/6) but differ in mitochondrial genomes (C57 or NZB), lactation engages different transcriptional programs resulting in anti-tumorigenic lactation in BL/6C57 females and pro-tumorigenic lactation in BL/6NZB females. Our data indicate activation of a pro-apoptotic ER-stress response during lactation in BL/6C57 females but an anti-apoptotic ER-stress response in BL/6NZB females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6NZB females, that shares the genetic signature of post-partum breast cancer in humans (PPBC) and is characterized by cell cycle markers and loss of p53. We show that pharmacological manipulations of ER-stress directly affect this signature. Overall, our data reveals the unexpected idiosyncratic nature of lactation and its impacts on the risk of the development of PPBC.