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Differential ER stress responses during lactation and postpartum outcomes in mice depending on their mitochondrial genotype

Author

Listed:
  • Mrittika Chattopadhyay

    (Division of Hematology/ Oncology)

  • Edmund Charles Jenkins

    (Division of Hematology/ Oncology)

  • William Janssen

    (Microscopy and Advanced Bioimaging Core)

  • Thelma Mashaka

    (Division of Hematology/ Oncology)

  • Doris Germain

    (Division of Hematology/ Oncology)

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.

Suggested Citation

  • Mrittika Chattopadhyay & Edmund Charles Jenkins & William Janssen & Thelma Mashaka & Doris Germain, 2025. "Differential ER stress responses during lactation and postpartum outcomes in mice depending on their mitochondrial genotype," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61666-5
    DOI: 10.1038/s41467-025-61666-5
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    References listed on IDEAS

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    1. Rahul Gupta & Masahiro Kanai & Timothy J. Durham & Kristin Tsuo & Jason G. McCoy & Anna V. Kotrys & Wei Zhou & Patrick F. Chinnery & Konrad J. Karczewski & Sarah E. Calvo & Benjamin M. Neale & Vamsi K, 2023. "Nuclear genetic control of mtDNA copy number and heteroplasmy in humans," Nature, Nature, vol. 620(7975), pages 839-848, August.
    2. Sonali Jindal & Nathan D. Pennock & Duanchen Sun & Wesley Horton & Michelle K. Ozaki & Jayasri Narasimhan & Alexandra Q. Bartlett & Sheila Weinmann & Paul E. Goss & Virginia F. Borges & Zheng Xia & Pe, 2021. "Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Ana Latorre-Pellicer & Raquel Moreno-Loshuertos & Ana Victoria Lechuga-Vieco & Fátima Sánchez-Cabo & Carlos Torroja & Rebeca Acín-Pérez & Enrique Calvo & Esther Aix & Andrés González-Guerra & Angela L, 2016. "Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing," Nature, Nature, vol. 535(7613), pages 561-565, July.
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