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 ( or ), lactation engages different transcriptional programs resulting in anti-tumorigenic lactation in BL/6 females and pro-tumorigenic lactation in BL/6 females. Our data indicate activation of a pro-apoptotic endoplasmic reticulum-stress response during lactation in BL/6 females, which is not observed in BL/6 females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6 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.