title: Poor prognosis in carcinoma is associated with a gene 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.
authors: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors: Lao H
authors: LH
authors: Saal
authors: Peter
authors: P
authors: Johansson
authors: Karolina
authors: K
authors: Holm
authors: Sofia K
authors: SK
authors: Gruvberger-Saal
authors: Qing-Bai
authors: QB
authors: She
authors: Matthew
authors: M
authors: Maurer
authors: Susan
authors: S
authors: Koujak
authors: Adolfo A
authors: AA
authors: Ferrando
authors: Per
authors: P
authors: Malmström
authors: Lorenzo
authors: L
authors: Memeo
authors: Jorma
authors: J
authors: Isola
authors: Pär-Ola
authors: PO
authors: Bendahl
authors: Neal
authors: N
authors: Rosen
authors: Hanina
authors: H
authors: Hibshoosh
authors: Markus
authors: M
authors: Ringnér
authors: Ake
authors: A
authors: Borg
authors: Ramon
authors: R
authors: Parsons
mesh_terms: D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human