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Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity
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- Saal, Lao (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Johansson, Peter (author)
- Lund University,Lunds universitet,Beräkningsbiologi och biologisk fysik - Genomgår omorganisation,Institutionen för astronomi och teoretisk fysik - Genomgår omorganisation,Naturvetenskapliga fakulteten,Computational Biology and Biological Physics - Undergoing reorganization,Department of Astronomy and Theoretical Physics - Undergoing reorganization,Faculty of Science
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- Holm, Karolina (author)
- Lund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- She, Qing-Bai (author)
- Maurer, Matthew (author)
- Koujak, Susan (author)
- Ferrando, Adolfo A. (author)
- Memeo, Lorenzo (author)
- Isola, Jorma (author)
- Rosen, Neal (author)
- Hibshoosh, Hanina (author)
- Parsons, Ramon (author)
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- (creator_code:org_t)
- 2007-05
- 2007
- English.
- In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 104:18, s. 7564-7569
- Journal article (peer-reviewed)
Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- stathmin
- breast cancer
- metastasis
- microarray
Publication and Content Type
- art (subject category)
- ref (subject category)
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- Isola, Jorma
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- Borg, Åke
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