RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

Dev Cell. 2021 Jun 21;56(12):1727-1741.e7. doi: 10.1016/j.devcel.2021.04.022. Epub 2021 May 17.


Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.

Keywords: breast cancer; mammary gland; metastasis; receptor activator of NFkB; senescence; senolytics; stemness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Transformation, Neoplastic / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • DNA Damage / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Experimental
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RANK Ligand / genetics*
  • Receptor Activator of Nuclear Factor-kappa B / genetics*


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFSF11 protein, human