title: Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy.
abstract: Prostatitis causes substantial morbidity to men, through associated urinary symptoms, sexual dysfunction, and pelvic pain; however, 90% to 95% of cases have an unknown etiology. Inflammation is associated with the development of carcinoma, and, therefore, it is imperative to identify and study the causes of prostatitis to improve our understanding of this disease and its role in prostate cancer. As estrogens cause prostatic inflammation, here we characterize the murine prostatic phenotype induced by elevated endogenous estrogens due to aromatase overexpression (AROM+). Early-life development of the AROM+ prostate was normal; however, progressive changes culminated in chronic inflammation and pre-malignancy. The AROM+ prostate was smaller at puberty compared with wild-type controls. Mast cell numbers were significantly increased at puberty and preceded chronic inflammation, which emerged by 40 weeks of age and was characterized by increased mast cell, macrophage, neutrophil, and T-lymphocyte numbers. The expression of key inflammatory mediators was also significantly altered, and premalignant prostatic intraepithelial neoplasia lesions emerged by 52 weeks of age. Taken together, these data link estrogens to prostatitis and premalignancy in the prostate, further implicating a role for estrogen in prostate cancer. These data also establish the AROM+ mouse as a novel, non-bacterial model for the study of prostatitis.
authors.affiliation: Centre for Urological Research, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia. Stuart.Ellem@med.monash.edu.au
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Ellem
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
mesh_terms: D000367:Age Factors; D000818:Animals; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D002908:Chronic Disease; D004195:Disease Models, Animal; D004967:Estrogens / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism; D011472:Prostatitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D004967:Estrogens; D001141:Aromatase
references.citation: J Urol. 1988 Nov;140(5):1049-53
references.pmid: 3172358
references.citation: Ann N Y Acad Sci. 2006 Nov;1089:1-13
references.pmid: 17261752
references.citation: Muscle Nerve. 2008 Jun;37(6):754-63
references.pmid: 18506708
references.citation: Dev Biol. 2001 Jan 15;229(2):432-42
references.pmid: 11150243
references.citation: Prostate Cancer Prostatic Dis. 2007;10(1):15-29
references.pmid: 17199136
references.citation: J Appl Physiol (1985). 2007 Jul;103(1):97-104
references.pmid: 17395758
references.citation: Endocrinology. 2006 Mar;147(3):1271-7
references.pmid: 16306085
references.citation: J Urol. 2002 Feb;167(2 Pt 1):753-6
references.pmid: 11792966
references.citation: Pathol Res Pract. 2002;198(4):267-71
references.pmid: 12049335
references.citation: Blood. 2003 Jan 1;101(1):210-5
references.pmid: 12393677
references.citation: Br J Cancer. 2007 Oct 8;97(7):952-6
references.pmid: 17848955
references.citation: Prostate. 2006 Feb 1;66(2):124-34
references.pmid: 16161154
references.citation: Prostate. 2007 Jun 1;67(8):888-99
references.pmid: 17440979
references.citation: Endocrinology. 2007 Feb;148(2):566-74
references.pmid: 17068134
references.citation: Dev Biol. 2001 Sep 1;237(1):145-58
references.pmid: 11518512
references.citation: Prostate. 1991;18(2):117-29
references.pmid: 2006118
references.citation: J Urol. 1998 Apr;159(4):1224-8
references.pmid: 9507840
references.citation: J Cancer Res Clin Oncol. 2008 Nov;134(11):1181-9
references.pmid: 18465142
references.citation: Prostate. 2000 Jun 15;44(1):19-25
references.pmid: 10861753
references.citation: Carcinogenesis. 2005 Jul;26(7):1170-81
references.pmid: 15498784
references.citation: J Urol. 2002 Jul;168(1):298-302
references.pmid: 12050560
references.citation: Gastroenterology. 1996 May;110(5):1482-90
references.pmid: 8613053
references.citation: Cancer Res. 2004 Mar 15;64(6):2270-305
references.pmid: 15026373
references.citation: Am J Pathol. 2006 Jun;168(6):1869-78
references.pmid: 16723702
references.citation: Br J Pharmacol. 2005 Aug;145(8):1062-8
references.pmid: 15937521
references.citation: J Pathol. 2005 May;206(1):52-61
references.pmid: 15772937
references.citation: J Biol Chem. 1997 Feb 28;272(9):5846-53
references.pmid: 9038201
references.citation: Cancer Res. 2001 Aug 15;61(16):6089-97
references.pmid: 11507058
references.citation: Br J Urol. 1982 Dec;54(6):729-31
references.pmid: 7150931
references.citation: Lancet. 2001 Feb 17;357(9255):539-45
references.pmid: 11229684
references.citation: J Cell Biochem. 2007 Jun 1;101(3):676-85
references.pmid: 17216598
references.citation: Development. 1991 Jan;111(1):145-58
references.pmid: 2015790
references.citation: J Intern Med. 2000 Sep;248(3):171-83
references.pmid: 10971784
references.citation: Prog Clin Biol Res. 1987;239:251-72
references.pmid: 3309957
references.citation: Epidemiology. 2002 Jan;13(1):72-9
references.pmid: 11805589
references.citation: Nature. 2002 Dec 19-26;420(6917):860-7
references.pmid: 12490959
references.citation: Mol Immunol. 2007 Mar;44(8):1977-85
references.pmid: 17084457
references.citation: Endocrinology. 2001 Jun;142(6):2458-67
references.pmid: 11356695
references.citation: FASEB J. 2008 May;22(5):1512-20
references.pmid: 18055862
references.citation: J Biol Chem. 2002 Nov 15;277(46):44475-84
references.pmid: 12191999
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Epidemiol Rev. 2001;23(1):144-51
references.pmid: 11588840
references.citation: J Clin Endocrinol Metab. 2004 May;89(5):2434-41
references.pmid: 15126575
references.citation: Cancer Res. 1991 Jul 1;51(13):3445-50
references.pmid: 1711411
references.citation: Prostate. 2007 Jan 1;67(1):14-21
references.pmid: 17075821
references.citation: J Urol. 1999 Aug;162(2):369-75
references.pmid: 10411041
references.citation: Med Hypotheses. 1984 May;14(1):29-39
references.pmid: 6748989
references.citation: J Infect Dis. 2007 Nov 1;196(9):1361-8
references.pmid: 17922401
references.citation: Endocrinology. 2002 Dec;143(12):4922-33
references.pmid: 12446620
references.citation: Gastroenterology. 1996 May;110(5):1656-8
references.pmid: 8613078
references.citation: Am J Pathol. 1999 Dec;155(6):1985-92
references.pmid: 10595928
references.citation: Reprod Toxicol. 1999 Nov-Dec;13(6):463-72
references.pmid: 10613394
references.citation: J Immunol. 2006 Feb 15;176(4):2238-48
references.pmid: 16455980
references.citation: Endocrinology. 2001 Jun;142(6):2435-42
references.pmid: 11356692