EGFR and HER2–Akt–mTOR signaling pathways are activated in subgroups of salivary gland carcinomas

• Published in: Virchows Archiv : an international journal of pathology Vol. 461; no. 3; pp. 271 - 282
• Main Authors: Suzuki, Shioto, Dobashi, Yoh, Minato, Hiroshi, Tajiri, Ryosuke, Yoshizaki, Tomokazu, Ooi, Akishi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.09.2012; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biomarkers, Tumor - metabolism; Carcinoma, Mucoepidermoid - genetics; Carcinoma, Mucoepidermoid - metabolism; Carcinoma, Mucoepidermoid - secondary; DNA, Neoplasm - analysis; Female; Gene Duplication; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Investigative techniques, diagnostic techniques (general aspects); Lymph Nodes - pathology; Lymphatic Metastasis; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Original Article; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - metabolism; Salivary Ducts - pathology; Salivary Gland Neoplasms - genetics; Salivary Gland Neoplasms - metabolism; Salivary Gland Neoplasms - pathology; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Tumors; mTOR; Akt; HER2; EGFR; Salivary gland carcinoma; Carcinoma; Digestive system; Akt protein kinase; erbB2 Gene; Salivary gland; Subgroup; Malignant tumor; Epidermal growth factor receptor; Human Epidermal growth factor Receptor 2; Anatomic pathology; Signaling pathway; C-Onc gene; Mammalian target of rapamycin; Protooncogene; Cancer
• ISSN: 0945-6317; 1432-2307
• DOI: 10.1007/s00428-012-1282-3

Salivary gland carcinomas encompass a wide spectrum of histological entities. To identify candidate therapeutic targets and innovative treatment options for these carcinomas, we examined epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), HER2, and phosphorylated forms of Akt (p-Akt) and mammalian target of rapamycin (p-mTOR) in 47 salivary gland tumors using immunohistochemistry. EGFR overexpression was found in 51 % of the tumors (24/47); in particular, EGFR overexpression occurred in mucoepidermoid (seven out of seven) and salivary duct carcinomas (9/12). Although EGFR amplification was not detected by fluorescence in situ hybridization analysis, increased copy number due to polysomy of chromosome 7, which houses EGFR , was observed in 4 of the 24 tumors with EGFR overexpression; this polysomy occurred most frequently in salivary duct carcinomas (three out of nine). HER2 overexpression was observed in 21 % (10/47) of all tumors; in these 10 tumors, HER2 gene amplification was found in seven cases. p-Akt was found in 51 % (24/47) of all tumors, most frequently in mucoepidermoid carcinomas (six out of seven). p-mTOR was found in 57 % of the latter (four out of seven). Consequently, different signaling cascades were found activated: (1) an EGFR/HER2(–Akt)–mTOR-dependent axis, with gene gains of HER2 and/or EGFR , activated in salivary duct carcinoma and carcinoma ex pleomorphic adenoma; (2) an EGFR(–Akt)–mTOR-dependent pathway activated in mucoepidermoid carcinoma or acinic cell carcinoma, without HER2 or EGFR gene alterations; and (3) an Akt-dependent pathway without EGFR/HER2 activation in other types. These findings indicate that phosphoprotein mapping of components in the EGFR/HER2–Akt–mTOR pathways may be a useful guide to select appropriate targeting regimens.