Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours

Nat Commun. 2017 Feb 13;8:14431. doi: 10.1038/ncomms14431.

Abstract

Most breast cancers may have a luminal origin. TP53 is one of the most frequently mutated genes in breast cancers. However, how p53 deficiency contributes to breast tumorigenesis from luminal cells remains elusive. Here we report that induced p53 loss in Krt8+ mammary luminal cells leads to their clonal expansion without directly affecting their luminal identity. All induced mice develop mammary tumours with 9qA1 (Yap1) and/or 6qA2 (Met) amplification(s). These tumours exhibit a mammary stem cell (MaSC)-like expression signature and most closely resemble claudin-low breast cancer. Thus, although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumours with loss of luminal identity. Our data also suggest that claudin-low breast cancer can develop from luminal cells, possibly via a basal-like intermediate state, although further study using a different luminal promoter is needed to fully support this conclusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Cell Cycle Proteins
  • Cell Proliferation / genetics*
  • Cell Transformation, Neoplastic / genetics*
  • Clone Cells
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Humans
  • Mammary Glands, Animal / metabolism*
  • Mammary Neoplasms, Animal / genetics*
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphoproteins / genetics
  • Proto-Oncogene Proteins c-met / genetics
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Tumor Suppressor Protein p53
  • Yap1 protein, mouse
  • Proto-Oncogene Proteins c-met