title: PTEN deficiency contributes to the development and progression of head and neck cancer.
abstract: The sequencing of the head and neck cancer has provided a blueprint of the most frequent genetic alterations in this cancer type. They include inactivating mutations in Notch, p53, and p16(ink4a) tumor suppressor genes, in addition to nonoverlapping activating mutations of the PIK3CA and RAS oncogenes or inactivation of the tumor suppressor gene PTEN. Notably, these genetic alterations, along with epigenetic changes, result in increased activity of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which is present in most head and neck squamous cell carcinomas (HNSCCs). Moreover, we show here that approximately 30% of HNSCCs exhibit reduced PTEN expression. We challenged the biologic relevance of this finding by combining the intraoral administration of a tobacco surrogate, 4-nitroquinoline 1-oxide, with a genetically defined animal model displaying reduced PTEN expression, achieved by the conditional deletion of Pten using the keratin promoter 14 CRE-lox system. This provided a specific genetic and environmentally defined animal model for HNSCC that resulted in the rapid development of oral-specific carcinomas. Under these experimental conditions, control mice did not develop HNSCC lesions. In contrast, most mice harboring Pten deficiency developed multiple SCC lesions in the lateral border and ventral part of the tongue and floor of the mouth, which are the preferred anatomic sites for human HNSCC. Overall, our study highlights the likely clinical relevance of reduced PTEN expression and/or inactivation in HNSCC progression, while the combined Pten deletion with exposure to tobacco carcinogens or their surrogates may provide a unique experimental model system to study novel molecular targeted treatments for HNSCC patients.
authors: Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109-1078, USA. csquarize@umich.edu
authors: Cristiane H
authors: CH
authors: Squarize
authors: Rogerio M
authors: RM
authors: Castilho
authors: Aline C
authors: AC
authors: Abrahao
authors: Alfredo
authors: A
authors: Molinolo
authors: Mark W
authors: MW
authors: Lingen
authors: J Silvio
authors: JS
authors: Gutkind
mesh_terms: D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000139:chemically induced / Q000378:metabolism* / Q000556:secondary; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018450:Disease Progression; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015112:4-Nitroquinoline-1-oxide; D051546:Cyclooxygenase 2; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C077623:Ptgs2 protein, mouse; C546843:mTOR protein, mouse; C494929:PTEN protein, human
references: Biochim Biophys Acta. 2005 Nov 25;1756(2):145-54
references: 16126346
references: Oncogene. 2010 Oct 7;29(40):5437-46
references: 20676130
references: Int J Cancer. 1998 Aug 31;77(5):684-8
references: 9688299
references: Nat Rev Cancer. 2006 Sep;6(9):729-34
references: 16915295
references: Br J Cancer. 1993 Sep;68(3):617-20
references: 8353052
references: Cancer Res. 2005 Apr 1;65(7):2554-9
references: 15805248
references: Nat Rev Genet. 2006 Aug;7(8):606-19
references: 16847462
references: Cell. 1998 Oct 2;95(1):29-39
references: 9778245
references: J Biol Chem. 1998 May 29;273(22):13375-8
references: 9593664
references: J Am Dent Assoc. 1968 Apr;76(4):767-71
references: 5238856
references: Oncogene. 2005 Feb 10;24(7):1244-51
references: 15558013
references: Cancer. 2001 Oct 1;92(7):1888-95
references: 11745262
references: Cancer Cell. 2004 May;5(5):489-500
references: 15144956
references: Cancer Sci. 2006 Dec;97(12):1351-8
references: 17052259
references: Science. 2011 Aug 26;333(6046):1157-60
references: 21798893
references: Cancer Cell. 2004 Apr;5(4):311-6
references: 15093538
references: Carcinogenesis. 2009 Mar;30(3):377-86
references: 19136477
references: Clin Cancer Res. 2007 Sep 1;13(17):4964-73
references: 17785546
references: Head Neck. 2006 Oct;28(10):945-54
references: 16721744
references: Cancer Genet Cytogenet. 2002 Jan 1;132(1):20-4
references: 11801303
references: N Engl J Med. 2007 May 10;356(19):1944-56
references: 17494927
references: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references: 22237781
references: Int J Oncol. 2008 Jan;32(1):101-11
references: 18097548
references: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4029-37
references: 15217935
references: Science. 2011 Aug 26;333(6046):1154-7
references: 21798897
references: Cancer Prev Res (Phila). 2009 Jan;2(1):27-36
references: 19139015
references: Oral Oncol. 2000 Jan;36(1):76-80
references: 10889924
references: Neoplasia. 2007 Feb;9(2):166-80
references: 17356713
references: Cancer Res. 2004 Dec 15;64(24):8804-7
references: 15604235
references: Cancer Res. 2008 Sep 1;68(17):7066-72
references: 18757421
references: Bull World Health Organ. 1967;37(1):109-16
references: 5300044
references: Cancer. 2005 Dec 1;104(11):2430-6
references: 16245318
references: Head Neck. 1994 Sep-Oct;16(5):424-32
references: 7960739
references: Nat Genet. 1998 Aug;19(4):348-55
references: 9697695
references: Br J Cancer. 1991 Apr;63(4):573-8
references: 2021541
references: Arch Otolaryngol Head Neck Surg. 2001 Dec;127(12):1441-5
references: 11735811
references: Nat Genet. 2007 Mar;39(3):347-51
references: 17293865
references: Oral Oncol. 2010 Dec;46(12):880-7
references: 20951077
references: PLoS One. 2010 May 13;5(5):e10643
references: 20498714
references: Cancer. 1953 Sep;6(5):963-8
references: 13094644
references: Cancer Epidemiol Biomarkers Prev. 2000 Mar;9(3):249-56
references: 10750662
references: Oncogene. 2004 Apr 1;23(14):2484-98
references: 14676830
references: Cell. 2000 Feb 18;100(4):387-90
references: 10693755
references: Nat Genet. 1999 Jan;21(1):70-1
references: 9916792
references: Cancer Prev Res (Phila). 2009 May;2(5):419-22
references: 19401522
references: PLoS One. 2010 May 06;5(5):e10503
references: 20463891
references: Biochemistry. 1990 Feb 27;29(8):2122-6
references: 2109634
references: J Oral Pathol Med. 2002 Aug;31(7):379-84
references: 12224530
references: Oral Oncol. 1999 Mar;35(2):157-63
references: 10435150
references: J Natl Cancer Inst. 1994 Jan 19;86(2):131-7
references: 8271296
references: Clin Cancer Res. 2006 Sep 1;12(17):5064-73
references: 16951222
references: Cancer Res. 2004 Jan 1;64(1):55-63
references: 14729608