Lao H. Saal, Peter Johansson,
Karolina Holm,
Sofia K. Gruvberger-Saal, Qing-Bai She,
Matthew Maurer, Susan Koujak,
Adolfo A. Ferrando, Per Malmström,
Lorenzo Memeo, Jorma Isola,
Pär-Ola Bendahl, Neil Rosen,
Hanina Hibshoosh, Markus Ringnér,
Åke Borg, and Ramon Parsons
Poor prognosis in carcinoma is associated with a gene
expression signature of aberrant PTEN tumor suppressor
pathway activity
Proceedings of the National Academy of Sciences
USA 104, 7564-7569 (2007)
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.
LU TP 06-18