Abstract
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 for the production of milk proteins and endoplasmic reticulum- 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 endoplasmic reticulum-stress response during lactation in BL/6C57 females, which is not observed 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 and is characterized by cell cycle markers and loss of p53. We show that pharmacological manipulations of endoplasmic reticulum-stress directly affect this signature. Overall, our data suggest the unexpected differential nature of lactation and its potential impact on the risk of the development of post-partum breast cancer.