Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis

Stem Cells. 2013 Sep;31(9):1954-65. doi: 10.1002/stem.1454.


Receptor Activator of NF-kappa B (RANK) pathway controls mammary gland development in mice but its role in mammary stem cell fate remains undefined. We show that constitutive RANK signaling expands luminal and basal mammary compartments including mammary stem and luminal progenitor cell pools and interferes with the generation of CD61+ and Sca1+ luminal cells and Elf5 expression. Impaired mammary cell commitment upon RANK overexpression leads to the accumulation of progenitors including K14+K8+ bipotent cells and the formation of heterogeneous tumors containing hyperplastic basal, luminal, and progenitor cells. RANK expression increases in wild-type mammary epithelia with age and parity, and spontaneous preneoplastic lesions express RANK and accumulate K14+K8+ cells. In human breast tumors, high RANK expression levels are also associated with altered mammary differentiation. These results suggest that increased RANK signaling interferes with mammary cell commitment, contributing to breast carcinogenesis.

Keywords: Bipotent progenitors; Breast adenocarcinomas; CD61; Mammary stem cell fate; RANK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Aging / pathology
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology*
  • Cell Compartmentation
  • Cell Differentiation
  • Cell Lineage*
  • Cell Shape
  • Epithelium / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Keratins / metabolism
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Tumor Virus, Mouse / physiology
  • Mice
  • Models, Biological
  • Parity
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Pregnancy
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Stem Cells / metabolism


  • Receptor Activator of Nuclear Factor-kappa B
  • Keratins