title: Functional characterization of epithelial ovarian cancer histotypes by drug target based protein signaling activation mapping: implications for personalized cancer therapy.
abstract: Epithelial ovarian carcinoma (EOC) is a deadly disease, with a 5-year survival of 30%. The aim of the study was to perform broad-scale protein signaling activation mapping to evaluate if EOC can be redefined based on activated protein signaling network architecture rather than histology. Tumor cells were isolated using laser capture microdissection (LCM) from 72 EOCs. Tumors were classified as serous (n = 38), endometrioid (n = 13), mixed (n = 8), clear cell (CCC; n = 7), and others (n = 6). LCM tumor cells were lysed and subjected to reverse-phase protein microarray to measure the expression/activation level of 117 protein drug targets. Unsupervised hierarchical clustering analysis was utilized to explore the overall signaling network. ANOVA was used to detect significant differences among the groups (p < 0.05). Regardless of histology, unsupervised analysis revealed five pathway-driven clusters. When the EOC histotypes were compared by ANOVA, only CCC showed a distinct signaling network, with activation of EGFR, Syk, HER2/ErbB2, and SHP2 (p = 0.0007, p = 0.0021, p < 0.0001, and p = 0.0410, respectively). The histological classification of EOC fails to adequately describe the underpinning protein signaling network. Nevertheless, CCC presents unique signaling characteristics compared to the other histotypes. EOC may need to be characterized by functional signaling activation mapping rather than pure histology.
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Maria Isabella
authors.initials: MI
authors.lastname: Sereni
authors.forename: Elisa
authors.initials: E
authors.lastname: Baldelli
authors.forename: Guido
authors.initials: G
authors.lastname: Gambara
authors.forename: Jianghong
authors.initials: J
authors.lastname: Deng
authors.forename: Laura
authors.initials: L
authors.lastname: Zanotti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bandiera
authors.forename: Eliana
authors.initials: E
authors.lastname: Bignotti
authors.forename: Monica
authors.initials: M
authors.lastname: Ragnoli
authors.forename: Germana
authors.initials: G
authors.lastname: Tognon
authors.forename: Antonella
authors.initials: A
authors.lastname: Ravaggi
authors.forename: Francesco
authors.initials: F
authors.lastname: Meani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Memo
authors.forename: Roberto
authors.initials: R
authors.lastname: Angioli
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
authors.forename: Sergio L
authors.initials: SL
authors.lastname: Pecorelli
authors.forename: Emanuel
authors.initials: E
authors.lastname: Petricoin
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Pierobon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077216:Carcinoma, Ovarian Epithelial; D066246:ErbB Receptors / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D057285:Precision Medicine; D040081:Protein Array Analysis; D060066:Protein Interaction Maps; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000032:analysis / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D055815:Young Adult
chemical_list: D066246:ErbB Receptors; D047908:Intracellular Signaling Peptides and Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000072377:Syk Kinase; C512478:EGFR protein, human; C000606896:SYK protein, human
keywords: Clear cell carcinoma; HER2/ErbB2; Ovarian cancer; Phosphorylation; Protein arrays