PI3K Pathway Effectors pAKT and FOXO1 as Novel Markers of Endometrioid Intraepithelial Neoplasia

Abstract

The diagnosis of endometrioid intraepithelial neoplasia (EIN) is challenging owing to limited sampling, hormonal status, and other confounding histologic variables. Markers such as PTEN or PAX2 can delineate EIN in some cases, but are not wholly reliable. Clearly, new markers of EIN are needed. We explored several potential markers of EIN based rationally on molecular pathways most frequently misregulated in endometrial cancer: the 3-phosphoinositide kinase (PI3K)/AKT, β-catenin, and mismatch repair pathways. We studied PTEN, PAX2, β-catenin, and MLH1, in conjunction with 2 new markers—FOXO1 and phosphorylated AKT (pAKT)—not previously investigated in EIN. Benign (n=14) and EIN (n=35) endometria were analyzed by immunohistochemistry. Staining patterns were interpreted, tabulated, and scored by “clonal distinctiveness” in neoplastic lesions; that is, pattern alterations relative to normal glands. In normal endometria, FOXO1 was cytoplasmic in proliferative phase, but nuclear in secretory phase, showing that PI3K/FOXO1 participates in endometrial cycling and that FOXO1 is a readout of PI3K status. pAKT expression was low across normal endometria. FOXO1 or pAKT expression was altered in the majority of EINs (27/35, 77%), with FOXO1 and pAKT being co-altered only in some (20/35, 57%). β-catenin or MLH1 also exhibited clonal distinctiveness in EINs, showing that these are also useful markers in some cases. This is the first study to demonstrate the potential of pAKT and FOXO1 as biomarkers in the histopathologic evaluation of EIN. However, variability in expression poses challenges in interpretation.

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

“…By 6 wk, Pten was lost in ∼50% of epithelial cells, and these clones also showed increased p-Akt(Ser473), consistent with Akt hyperactivation. This led to complete relocalization of the transcription factor and Akt target Foxo1 from the nucleus to the cytoplasm, as occurs in human endometrial precancers and other PI3K-dependent developmental and reproductive processes (32–34). By 12 wk, Fbxw7/Pten uteri showed an increased percentage of Pten -null cells relative to Pten alone ( P = 0.027, t test), showing that Fbxw7 and Pten loss act synergistically in conferring a growth advantage to endometrial epithelial cells ( SI Appendix , Fig.…”

Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells

“…pAKT is an important biomarker for human cancer [22][23][24][25]. To establish pAKT as a direct phosphorylation target of MER kinase, we developed a MER cellular assay and compared the inhibition of MER activation and AKT phosphorylation.…”

Genomic Comparison of Endometrioid Endometrial Carcinoma and Its Precancerous Lesions in Chinese Patients by High-Depth Next Generation Sequencing

“…Alterations in PI3K/AKT/mTOR signaling pathway are very common in endometrial carcinoma and its precursor lesions ( 17 , 18 ). Of the genes involved in this pathway examined in our study, PTEN, PIK3CA, and PIK3R1 all mutated frequently, which was similar to the TCGA study on endometrial carcinoma ( 4 ).…”