Functional characterization of novel presenilin-2 variants identified in human breast cancers

Oncogene. 2006 Jun 15;25(25):3557-64. doi: 10.1038/sj.onc.1209397. Epub 2006 Feb 13.


We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Abeta(42)/Abeta(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Cell Proliferation
  • DNA Mutational Analysis
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation
  • Humans
  • Immunoprecipitation
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Polymorphism, Single-Stranded Conformational
  • Presenilin-2


  • Membrane Proteins
  • PSEN2 protein, human
  • Presenilin-2