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

被引:420
作者
Saal, Lao H.
Johansson, Peter
Holm, Karolina
Gruvberger-Saal, Sofia K.
She, Qing-Bai
Maurer, Matthew
Koujak, Susan
Ferrando, Adolfo A.
Malmstrom, Per
Memeo, Lorenzo
Isola, Jorma
Bendahl, Par-Ola
Rosen, Neal
Hibshoosh, Hanina
Ringner, Markus
Borg, Ake
Parsons, Ramon [1 ]
机构
[1] Columbia Univ, Inst Canc Genet, Dept Pathol, Herbert Irving Comprehens Canc Ctr,Coll Phys, New York, NY 10032 USA
[2] Columbia Univ, Inst Canc Genet, Dept Med, Herbert Irving Comprehens Canc Ctr,Coll Phys, New York, NY 10032 USA
[3] Columbia Univ, Inst Canc Genet, Dept Pediat, Herbert Irving Comprehens Canc Ctr,Coll Phys, New York, NY 10032 USA
[4] Lund Univ, Dept Oncol, SE-22185 Lund, Sweden
[5] Lund Univ, Dept Theoret Phys, SE-22185 Lund, Sweden
[6] Lund Univ, Lund Strateg Res Ctr Stem Biol & Cell Therapy, SE-22185 Lund, Sweden
[7] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA
[8] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA
[9] Tampere Univ, Inst Med Technol, FIN-37520 Tampere, Finland
关键词
breast cancer; metastasis; stathmin; microarray;
D O I
10.1073/pnas.0702507104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (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-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.
引用
收藏
页码:7564 / 7569
页数:6
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