Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice

Nat Cell Biol. 2015 Mar;17(3):217-27. doi: 10.1038/ncb3118. Epub 2015 Feb 23.

Abstract

Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cell-extrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11-fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp1/Timp3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aging / genetics*
  • Aging / metabolism
  • Animals
  • Cell Differentiation
  • Cell Proliferation / genetics*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism
  • Mice
  • Mice, Knockout
  • Mitosis
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Risk Factors
  • Signal Transduction
  • Spindle Apparatus / metabolism
  • Spindle Apparatus / pathology
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / deficiency
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-3 / deficiency
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*

Substances

  • Cytoskeletal Proteins
  • Receptors, Notch
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-3