Luminal progenitors restrict their lineage potential during mammary gland development

PLoS Biol. 2015 Feb 17;13(2):e1002069. doi: 10.1371/journal.pbio.1002069. eCollection 2015 Feb.

Abstract

The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage / genetics*
  • Cell Tracking
  • Epithelial Cells / cytology*
  • Epithelial Cells / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Knock-In Techniques
  • Integrases / genetics
  • Integrases / metabolism
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Transgenic
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / metabolism
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Organogenesis / genetics*
  • Phenotype
  • Pregnancy
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism

Substances

  • Estrogen Receptor alpha
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Cre recombinase
  • Integrases

Grants and funding

This work was in part supported by the Association pour la Recherche contre le Cancer, grant Number SFI20111203777 (http://www.recherche-cancer.net/), the Ligue contre le Cancer, grant Number RS14/75-87 (http://www.ligue-cancer.net/) and by Labex DEEP ANR-Number 11-LBX-0044 (http://www.labex-deep.fr/?lang=en) to SF. VR was funded by a post-doctoral fellowship from Association pour la Recherche contre le Cancer, dossier n° PDF20111204419 (http://www.recherche-cancer.net/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.