title: Endometrial cancer cells exhibit high expression of p110β and its selective inhibition induces variable responses on PI3K signaling, cell survival and proliferation.
abstract: PTEN loss and constitutive activation of the class I phosphoinositide 3-kinase (PI3K) pathway are key drivers of endometrial tumorigenesis. In some cancer types, PTEN-deficient tumors are reliant on class I PI3K p110β (encoded by PIK3CB) activity but little is known about this contribution in endometrial tumorigenesis. In this study, we find that p110β is overexpressed in a panel of 7 endometrial cancer cell lines compared to non-transformed cells. Furthermore, in 234 clinically annotated patient samples, PIK3CB mRNA levels increase significantly in the early phase of tumorigenesis from precursors to low grade primary malignant lesions whereas PIK3CA levels are higher in non-endometrioid compared to endometrioid primary tumors. While high levels of either PIK3CA or PIK3CB associate with poor prognosis, only elevated PIK3CB mRNA levels correlate with a high cell cycle signature score in clinical samples. In cancer cell lines, p110α inhibition reduces cell viability by inducing cell death in PIK3CA mutant cells while p110β inhibition delayed proliferation in PTEN-deficient cells, but not in WT cells. Taken together, our findings suggest that PIK3CB/p110β contributes to some of the pleiotropic functions of PI3K in endometrial cancer, particularly in the early steps by contributing to cell proliferation.
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karlsson
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ingvild Løberg
authors.initials: IL
authors.lastname: Tangen
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Queensland University of Technology, Brisbane, Australia.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
authors.affiliation: Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.affiliation: Department of Molecular Biology, University of Bergen, Bergen, Norway.
authors.forename: Aurélia E
authors.initials: AE
authors.lastname: Lewis
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011744:Pyrimidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D009025:Morpholines; D011744:Pyrimidinones; C504718:TGX 221; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human
keywords: PI3K inhibitors; PIK3CB; PTEN; endometrial cancer; p110β