Idiosyncratic nature of lactation reveals link to breast cancer risk.
Doris GermainMrittika ChattopadhyayEdmund JenkinsWilliam JanssenThelma MashakaPublished in: Research square (2024)
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), the biological processes engaged during lactation are entirely different at the sub-cellular organization and transcriptional levels resulting in anti-tumorigenic lactation in BL/6C57 females and pro-tumorigenic lactation in BL/6NZB females. Single cell sequencing identified a sub-population of cells, uniquely amplified during lactation in BL/6NZB females, which shares the genetic signature that characterizes post-partum breast cancer (PPBC) in humans relative to matched breast cancers in never pregnant women. Our data indicate that differences in ER and mitochondrial-stress responses during lactation between genotypes inadvertently leads to loss of p53 tumor suppressor function in BL/6NZB females allowing the expansion of the PPBC-like sub-population of cells. Overall, our data reveals the unexpected idiosyncratic nature of lactation and its impacts on the risk of the development of PPBC.
Keyphrases
- dairy cows
- human milk
- endoplasmic reticulum
- breast cancer risk
- pregnant women
- single cell
- low birth weight
- induced apoptosis
- preterm infants
- genome wide
- gene expression
- rna seq
- dna methylation
- estrogen receptor
- type diabetes
- polycystic ovary syndrome
- insulin resistance
- copy number
- high throughput
- metabolic syndrome
- transcription factor
- cell death
- anti inflammatory
- young adults
- heat shock protein
- heat shock