Genomics

Dataset Information

67

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


ABSTRACT: Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, 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 (BC). 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-PI3K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K 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: Disease state analysis Overall design: 105 breast cancer tumor samples were analyzed on 2-color cDNA microarrays using the Stratagene Universal Human Reference RNA as the common reference sample.

INSTRUMENT(S): Swegene Human 27K RAP UniGene188 array

SUBMITTER: Lao H Saal  

PROVIDER: GSE5325 | GEO | 2007-04-07

SECONDARY ACCESSION(S): PRJNA96337

REPOSITORIES: GEO

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

Saal Lao H LH   Johansson Peter P   Holm Karolina K   Gruvberger-Saal Sofia K SK   She Qing-Bai QB   Maurer Matthew M   Koujak Susan S   Ferrando Adolfo A AA   Malmström Per P   Memeo Lorenzo L   Isola Jorma J   Bendahl Pär-Ola PO   Rosen Neal N   Hibshoosh Hanina H   Ringnér Markus M   Borg Ake A   Parsons Ramon R  

Proceedings of the National Academy of Sciences of the United States of America 20070423 18


Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN los  ...[more]

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