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.breast cancer ͉ metastasis ͉ stathmin ͉ microarray

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…Stathmin protein expression has been associated with PI3Kinase activity in breast and endometrial cancers. 96,118 The latter found STMN1 overexpressed in 15% of Type I cancers compared to 64% for Type II. 96 Other oncogenes have also been reported as altered in endometrial cancer; Drug sensitive mutations in the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene have been reported in 12% of endometrial carcinomas.…”

“…118 For AKT immunohistochemical staining, no correlations with clinico-pathological factors and survival have been reported from several studies investigating breast-, gastric-and bronchial cancers. [205][206][207] Our study of endometrial carcinomas adds to this general impression that AKT is not valuable as a cancer prognosticator.…”

“…Stathmin has been found to correlate with aggressive clinico-pathological features and poor prognosis in several cancers 115 as breast- 118,208 , ovarian-209 and cervical cancers. 210 One study supported Stathmin as a surrogate marker of PI3Kinase pathway activation, and of independent prognostic value.…”

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

“…The MX-1 (also known as Bx11), Bx15 and Bx33 breast cancer xenografts have been described 21 . PTEN protein blotting was performed as described 14 .…”

“…Despite these advances in delineating BBC, the molecular lesions and oncogenic signaling pathways that drive BBC and the precise oncogenic consequences of BRCA1-mediated basal-like tumorigenesis are incompletely known. The phosphatidylinositol 3-kinase (PI3K) pathway is a potent oncogenic signaling cascade that promotes cell transformation, proliferation, migration, angiogenesis and genomic instability; inhibits apoptosis; maintains stem cell compartments; and is associated with poor prognosis in carcinoma [11][12][13][14] . PTEN is the crucial tumor suppressor in this pathway because it catalyzes the precise opposite reaction to PI3K, thereby inhibiting downstream signaling 12 .…”