title: Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males.
abstract: The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1(-/-)) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.forename: Michael D
authors.initials: MD
authors.lastname: Brooks
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.forename: Steven C
authors.initials: SC
authors.lastname: Snyder
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Sengupta
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001932:Brain Neoplasms / Q000453:epidemiology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016514:Genes, Neurofibromatosis 1; D016158:Genes, p53; D005909:Glioblastoma / Q000453:epidemiology* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D015995:Prevalence; D016160:Retinoblastoma Protein / Q000502:physiology*; D012727:Sex Characteristics
chemical_list: D016160:Retinoblastoma Protein; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
references.citation: J Clin Neurosci. 2009 Jun;16(6):748-54
references.pmid: 19324552
references.citation: Cancer Res. 2012 Jan 1;72(1):122-32
references.pmid: 22052462
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Cell. 1994 Jul 15;78(1):161-72
references.pmid: 8033208
references.citation: Nature. 2009 Aug 27;460(7259):1140-4
references.pmid: 19668186
references.citation: Nat Rev Genet. 2008 Dec;9(12):911-22
references.pmid: 19002143
references.citation: Genes Dev. 2012 Jul 1;26(13):1409-20
references.pmid: 22751497
references.citation: Oncogene. 2001 Oct 25;20(48):6983-93
references.pmid: 11704823
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13008-13
references.pmid: 15319471
references.citation: Cancer Res. 2007 Jan 15;67(2):651-8
references.pmid: 17234775
references.citation: Acta Neuropathol. 2012 Apr;123(4):465-72
references.pmid: 22134537
references.citation: Cancer Cell. 2005 Aug;8(2):119-30
references.pmid: 16098465
references.citation: Oncogene. 2005 Nov 21;24(52):7729-45
references.pmid: 16299533
references.citation: Cancer Res. 2010 Jul 15;70(14):5717-27
references.pmid: 20551058
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Science. 2012 Nov 23;338(6110):1080-4
references.pmid: 23087000
references.citation: Mamm Genome. 2009 Apr;20(4):214-23
references.pmid: 19347398
references.citation: J Immunol Methods. 2009 Aug 15;347(1-2):70-8
references.pmid: 19567251
references.citation: Cancer Res. 2007 Sep 15;67(18):8588-95
references.pmid: 17875698
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2712-6
references.pmid: 19196966
references.citation: Oncogene. 2002 Jul 4;21(29):4577-86
references.pmid: 12085236
references.citation: Cancer Res. 2009 Dec 1;69(23):9065-72
references.pmid: 19920198
references.citation: J Virol. 2009 Sep;83(18):9521-31
references.pmid: 19570859
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6
references.pmid: 22323597
references.citation: J Neurosci Methods. 2010 May 30;189(1):56-64
references.pmid: 20347873
references.citation: Oncogene. 2005 Apr 18;24(17):2796-809
references.pmid: 15838516
references.citation: Cell Growth Differ. 1999 Feb;10(2):73-86
references.pmid: 10074901
references.citation: Biol Sex Differ. 2012 Jan 25;3:3
references.pmid: 22277186
references.citation: Acta Neuropathol. 2012 Apr;123(4):473-84
references.pmid: 22358457
references.citation: Neuro Oncol. 2012 Feb;14(2):160-74
references.pmid: 22234937
references.citation: PLoS One. 2008 Jul 02;3(7):e2553
references.pmid: 18596936
references.citation: Front Neuroendocrinol. 2009 Jan;30(1):1-9
references.pmid: 19028515
references.citation: Chin J Cancer. 2011 Sep;30(9):590-602
references.pmid: 21880180
references.citation: Cell. 2011 Jul 22;146(2):209-21
references.pmid: 21737130
references.citation: Mol Cell Biol. 2002 Jul;22(14):5100-13
references.pmid: 12077339
references.citation: Nat Genet. 2000 Sep;26(1):109-13
references.pmid: 10973261
references.citation: Br J Ophthalmol. 2009 Jan;93(1):24-7
references.pmid: 18718969
references.citation: Prog Cell Cycle Res. 1995;1:9-19
references.pmid: 9552350
references.citation: Nat Biotechnol. 1997 Sep;15(9):871-5
references.pmid: 9306402
references.citation: Cancer Cell. 2006 Mar;9(3):157-73
references.pmid: 16530701
references.citation: J Neurosci. 2005 Jun 8;25(23):5584-94
references.pmid: 15944386
references.citation: Biotechniques. 2005 May;38(5):702, 704, 706
references.pmid: 15945368
references.citation: BMC Cancer. 2011 Jul 29;11:325
references.pmid: 21801393
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1093-8
references.pmid: 19144918
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1430-7
references.pmid: 17553849
references.citation: Am J Surg Pathol. 2006 May;30(5):657-64
references.pmid: 16699322