Dysregulated PTEN-PKB and negative receptor status in human breast cancer

Int J Cancer. 2003 Mar 20;104(2):195-203. doi: 10.1002/ijc.10909.


Recent studies demonstrate that abnormalities in PTEN may be one of the most frequent genetic events observed in human cancers. PTEN dysfunction leads to tumorigenesis through unopposed survival signals mediated via activated protein kinase B (PKB), which may also be associated with hormone-independence. We therefore investigated the relationship between PTEN-PKB and receptor status in human breast cancer. Several molecular variables, including immunohistochemical staining for PTEN, PKB (phosphorylated on ser473), p53 and p21 were evaluated. The p53 gene was sequenced from exons 2-11. Seventy-eight participants in a randomised breast cancer trial served as the cohort for our study. Twenty-eight of 77 (36%) patients' tumours demonstrated absent or reduced PTEN expression; 17 of 78 (22%) tumours over-expressed P-PKB. A significant inverse relationship was observed between reduced PTEN and increased P-PKB expression. Reduced PTEN also correlated with reduced ER or PR expression. None of the molecular variables correlated with survival. ER and PR negative tumours, however, experienced a significantly inferior disease-free survival than other ER/PR status tumours. Immunohistochemical analyses of ER expression in mammary carcinomas arising in PTEN heterozygous knockout mice did not demonstrate a reduction in ER immunoreactivity, in comparison to wild-type mice. Our data demonstrate that the PTEN-PKB pathway is abnormal in approximately 1/3 of lymph node negative breast cancer. Dysregulated PTEN-PKB was also associated with reduced ER/PR expression, but this does not appear to be a simple direct causal relationship. These observations support the contention that dysregulation in PTEN-PKB contributes to disease progression and hormone resistance of human breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Female
  • Humans
  • Immunohistochemistry
  • Mammary Glands, Animal / metabolism
  • Mice
  • Middle Aged
  • Mutation
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*
  • Survival Analysis
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Proto-Oncogene Proteins
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human