title: Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα(+) tumorigenesis.
abstract: We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-α-positive (ERα(+)) breast cancers and mice lacking STAT1 spontaneously develop ERα(+) mammary tumors. However, the precise mechanism by which STAT1 suppresses mammary gland tumorigenesis has not been fully elucidated. Here we show that STAT1-deficient mammary epithelial cells (MECs) display persistent prolactin receptor (PrlR) signaling, resulting in activation of JAK2, STAT3 and STAT5A/5B, expansion of CD61(+) luminal progenitor cells and development of ERα(+) mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1(-/-) MECs. Prophylactic use of a pharmacological JAK2 inhibitor restrains the proportion of luminal progenitors and prevents disease induction. Systemic inhibition of activated JAK2 induces tumor cell death and produces therapeutic regression of pre-existing endocrine-sensitive and refractory mammary tumors. Thus, STAT1 suppresses tumor formation in mammary glands by preventing the natural developmental function of a growth factor signaling pathway from becoming pro-oncogenic. In addition, targeted inhibition of JAK2 may have significant therapeutic potential in controlling ERα(+) breast cancer in humans.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Chan
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Rickert
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA [2] Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia School of Medicine, Piazzale Spedali Civili 1, Brescia 25123, Italy.
authors.forename: W
authors.initials: W
authors.lastname: Vermi
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: K C F
authors.initials: KC
authors.lastname: Sheehan
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: C
authors.initials: C
authors.lastname: Arthur
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Allen
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: White
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: J
authors.initials: J
authors.lastname: Archambault
authors.affiliation: Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia School of Medicine, Piazzale Spedali Civili 1, Brescia 25123, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Oncology Drug Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: McDevitt
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: D
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Oncology Drug Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Lorenzi
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Allred
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425S Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D006575:Heterocyclic Compounds, 3-Ring; C571029:N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2
references.citation: Cancer Cell. 2009 Dec 8;16(6):487-97
references.pmid: 19962667
references.citation: Mol Endocrinol. 1997 Jul;11(8):1180-8
references.pmid: 9212064
references.citation: Oncogene. 2010 Sep 30;29(39):5359-69
references.pmid: 20639901
references.citation: Mol Cell Endocrinol. 1996 Mar 25;117(2):131-40
references.pmid: 8737372
references.citation: Oncotarget. 2011 Dec;2(12):1043-54
references.pmid: 22185785
references.citation: Mol Endocrinol. 2008 Aug;22(8):1825-41
references.pmid: 18499741
references.citation: J Mammary Gland Biol Neoplasia. 2008 Mar;13(1):41-53
references.pmid: 18246319
references.citation: Cell. 1998 May 29;93(5):841-50
references.pmid: 9630227
references.citation: Oncogene. 2001 May 3;20(20):2499-513
references.pmid: 11420660
references.citation: Mol Endocrinol. 1996 Dec;10(12):1496-506
references.pmid: 8961260
references.citation: Mol Cell Biol. 2004 Sep;24(18):8037-47
references.pmid: 15340066
references.citation: J Mammary Gland Biol Neoplasia. 2008 Mar;13(1):29-40
references.pmid: 18219562
references.citation: J Clin Endocrinol Metab. 1997 Nov;82(11):3692-9
references.pmid: 9360527
references.citation: J Immunol Methods. 2009 Aug 15;347(1-2):70-8
references.pmid: 19567251
references.citation: Genes Dev. 1997 Jan 15;11(2):179-86
references.pmid: 9009201
references.citation: Mol Endocrinol. 2002 May;16(5):1108-24
references.pmid: 11981045
references.citation: J Mammary Gland Biol Neoplasia. 2008 Mar;13(1):147-56
references.pmid: 18246318
references.citation: Recent Prog Horm Res. 2003;58:297-323
references.pmid: 12795425
references.citation: Oncogene. 2004 Oct 7;23(46):7726-33
references.pmid: 15361843
references.citation: Cancer Res. 2005 Feb 1;65(3):681-5
references.pmid: 15705859
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4138-43
references.pmid: 12640143
references.citation: Mol Cancer Res. 2009 Jun;7(6):966-76
references.pmid: 19491198
references.citation: Breast Cancer Res. 2012 Jan 20;14(1):R16
references.pmid: 22264274
references.citation: Semin Cell Dev Biol. 2008 Aug;19(4):401-6
references.pmid: 18723104
references.citation: Lancet. 2005 May 14-20;365(9472):1687-717
references.pmid: 15894097
references.citation: Mol Immunol. 2009 Jul;46(11-12):2151-60
references.pmid: 19482358
references.citation: Int J Cancer. 2004 Feb 20;108(5):665-71
references.pmid: 14696092
references.citation: Mol Cell Endocrinol. 1999 Dec 20;158(1-2):45-54
references.pmid: 10630404
references.citation: Nature. 2006 Feb 23;439(7079):993-7
references.pmid: 16395311
references.citation: J Biol Chem. 1999 Aug 27;274(35):24497-502
references.pmid: 10455112
references.citation: Nat Rev Cancer. 2009 Nov;9(11):798-809
references.pmid: 19851315
references.citation: Mol Cell Biol. 2007 Jul;27(13):4603-16
references.pmid: 17485448
references.citation: Endocr Rev. 1998 Jun;19(3):225-68
references.pmid: 9626554
references.citation: J Immunol. 2000 Jun 1;164(11):5833-43
references.pmid: 10820262
references.citation: Adv Immunol. 2005;87:61-122
references.pmid: 16102572
references.citation: Oncogene. 2003 Jul 24;22(30):4664-74
references.pmid: 12879011
references.citation: Nature. 2011 Oct 09;479(7372):189-93
references.pmid: 21983963
references.citation: J Clin Endocrinol Metab. 1998 Feb;83(2):667-74
references.pmid: 9467590
references.citation: Cell Death Differ. 2012 Mar;19(3):511-22
references.pmid: 21941370
references.citation: Cancer Cell. 2012 Dec 11;22(6):796-811
references.pmid: 23238015
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7174-8
references.pmid: 7518927
references.citation: J Immunol. 1989 Jun 1;142(11):3884-93
references.pmid: 2469726
references.citation: Neoplasia. 2010 Nov;12(11):899-905
references.pmid: 21076615
references.citation: Genes Dev. 1995 Apr 15;9(8):984-94
references.pmid: 7774815
references.citation: Genes Dev. 2009 Oct 15;23(20):2382-7
references.pmid: 19833766
references.citation: Mol Cell Biol. 2004 Jun;24(12):5510-20
references.pmid: 15169911
references.citation: Mol Endocrinol. 2006 May;20(5):1177-87
references.pmid: 16469767
references.citation: FEBS Lett. 1998 Dec 18;441(2):287-91
references.pmid: 9883901
references.citation: Leukemia. 2012 Feb;26(2):280-8
references.pmid: 22015772
references.citation: Cell Cycle. 2011 Mar 1;10(5):794-804
references.pmid: 21311224
references.citation: Nature. 2006 Jan 5;439(7072):84-8
references.pmid: 16397499
references.citation: Int J Cancer. 2004 Nov 20;112(4):607-19
references.pmid: 15382041
references.citation: Genes Dev. 2001 Jul 1;15(13):1631-6
references.pmid: 11445538
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6850-4
references.pmid: 8041708
references.citation: Genes Dev. 2003 May 15;17(10):1253-70
references.pmid: 12756227
references.citation: J Clin Invest. 2011 Jul;121(7):2723-35
references.pmid: 21633165