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

Saal, Lao LU ; Johansson, Peter LU ; Holm, Karolina LU ; Gruvberger, Sofia LU ; She, Qing-Bai; Maurer, Matthew; Koujak, Susan; Ferrando, Adolfo A.; Malmström, Per LU and Memeo, Lorenzo, et al. (2007) In Proceedings of the National Academy of Sciences 104(18). p.7564-7569
Abstract
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... (More)
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. (Less)
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publication status
published
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keywords
stathmin, breast cancer, metastasis, microarray
in
Proceedings of the National Academy of Sciences
volume
104
issue
18
pages
7564 - 7569
publisher
National Acad Sciences
external identifiers
  • wos:000246239400048
  • scopus:34250687198
ISSN
1091-6490
DOI
10.1073/pnas.0702507104
project
CREATE Health
language
English
LU publication?
yes
id
a00c4a70-c933-4d48-b933-3ef8a208043e (old id 661087)
date added to LUP
2007-12-21 14:39:05
date last changed
2017-11-12 03:31:03
@article{a00c4a70-c933-4d48-b933-3ef8a208043e,
  abstract     = {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.},
  author       = {Saal, Lao and Johansson, Peter and Holm, Karolina and Gruvberger, Sofia and She, Qing-Bai and Maurer, Matthew and Koujak, Susan and Ferrando, Adolfo A. and Malmström, Per and Memeo, Lorenzo and Isola, Jorma and Bendahl, Pär-Ola and Rosen, Neal and Hibshoosh, Hanina and Ringnér, Markus and Borg, Åke and Parsons, Ramon},
  issn         = {1091-6490},
  keyword      = {stathmin,breast cancer,metastasis,microarray},
  language     = {eng},
  number       = {18},
  pages        = {7564--7569},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity},
  url          = {http://dx.doi.org/10.1073/pnas.0702507104},
  volume       = {104},
  year         = {2007},
}