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Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity

Author:
  • Lao Saal
  • Peter Johansson
  • Karolina Holm
  • Sofia Gruvberger
  • Qing-Bai She
  • Matthew Maurer
  • Susan Koujak
  • Adolfo A. Ferrando
  • Per Malmström
  • Lorenzo Memeo
  • Jorma Isola
  • Pär-Ola Bendahl
  • Neal Rosen
  • Hanina Hibshoosh
  • Markus Ringnér
  • Åke Borg
  • Ramon Parsons
Publishing year: 2007
Language: English
Pages: 7564-7569
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 104
Issue: 18
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (P13K) pathway is frequently activated in solid tumors; however, currently, no reliable test for P13K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of P13K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (IBC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-P13K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant P13K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve.

Keywords

  • Cancer and Oncology
  • stathmin
  • breast cancer
  • metastasis
  • microarray

Other

Published
  • CREATE Health
  • ISSN: 1091-6490
Åke Borg
Åke Borg
E-mail: ake [dot] borg [at] med [dot] lu [dot] se

Principal investigator

Oncology and Pathology, MV

+46 46 275 25 52

MV 404 C21B2

90

Project manager

Familial Breast Cancer

90

Professor

Oncology and Pathology, MV

MV 404 C21C2

90