title: Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer.
abstract: Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Schaeffer
authors.forename: L
authors.initials: L
authors.lastname: Marchionni
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
authors.forename: B
authors.initials: B
authors.lastname: Simons
authors.forename: A
authors.initials: A
authors.lastname: Blackman
authors.forename: W
authors.initials: W
authors.lastname: Yu
authors.forename: G
authors.initials: G
authors.lastname: Parmigiani
authors.forename: D M
authors.initials: DM
authors.lastname: Berman
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011467:Prostate / Q000196:embryology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis
chemical_list: D000728:Androgens
references.citation: Exp Biol Med (Maywood). 2006 Jan;231(1):20-7
references.pmid: 16380641
references.citation: Cancer Cell. 2007 Dec;12(6):572-85
references.pmid: 18068633
references.citation: Curr Biol. 2005 Apr 26;15(8):702-13
references.pmid: 15854902
references.citation: Am J Physiol Heart Circ Physiol. 2007 Mar;292(3):H1278-90
references.pmid: 17071732
references.citation: Prostate Cancer Prostatic Dis. 2005;8(1):7-13
references.pmid: 15477876
references.citation: Clin Cancer Res. 2002 Jan;8(1):117-23
references.pmid: 11801547
references.citation: Nat Methods. 2005 May;2(5):345-50
references.pmid: 15846361
references.citation: Nature. 2002 Aug 22;418(6900):823
references.pmid: 12192390
references.citation: Reproduction. 2001 Feb;121(2):187-95
references.pmid: 11226043
references.citation: Dev Biol. 2004 Mar 15;267(2):387-98
references.pmid: 15013801
references.citation: Cancer Res. 2007 Jul 15;67(14):6535-8
references.pmid: 17638861
references.citation: Cold Spring Harb Symp Quant Biol. 2003;68:227-35
references.pmid: 15338622
references.citation: Nat Genet. 2007 Jan;39(1):41-51
references.pmid: 17173048
references.citation: Urol Oncol. 2006 May-Jun;24(3):231-6
references.pmid: 16678055
references.citation: Gene Expr Patterns. 2006 Mar;6(3):310-24
references.pmid: 16378759
references.citation: Nature. 1986 Oct 16-22;323(6089):643-6
references.pmid: 2877398
references.citation: Nature. 1976 Mar 11;260(5547):170-3
references.pmid: 176594
references.citation: Cancer Lett. 2006 Jun 8;237(1):22-32
references.pmid: 16023783
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11896-903
references.pmid: 12909713
references.citation: Dev Biol. 2007 Nov 1;311(1):124-35
references.pmid: 17904116
references.citation: Histochem Cell Biol. 2001 Nov;116(5):427-39
references.pmid: 11735006
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30
references.pmid: 18270516
references.citation: Genes Dev. 2004 Mar 15;18(6):629-40
references.pmid: 15075291
references.citation: Differentiation. 2007 Mar;75(3):219-34
references.pmid: 17288544
references.citation: Trends Mol Med. 2002 Jan;8(1):17-23
references.pmid: 11796262
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Nov;14(11 Pt 1):2563-8
references.pmid: 16284379
references.citation: Cancer Cell. 2007 Dec;12(6):559-71
references.pmid: 18068632
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15149-54
references.pmid: 11742071
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):181-6
references.pmid: 17185413
references.citation: Biol Reprod. 1980 Feb;22(1):9-17
references.pmid: 6991014
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):279-84
references.pmid: 11682119
references.citation: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6942-7
references.pmid: 15860580
references.citation: Prostate. 1987;11(3):229-42
references.pmid: 3684783
references.citation: Dev Biol. 2004 Sep 15;273(2):418-35
references.pmid: 15328023
references.citation: Genes Dev. 1999 Apr 15;13(8):966-77
references.pmid: 10215624
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):811-6
references.pmid: 14711987
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):107-37
references.pmid: 15863029
references.citation: Perspect Biol Med. 1968 Spring;11(3):371-5
references.pmid: 5704208
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Recent Prog Horm Res. 2002;57:385-409
references.pmid: 12017554
references.citation: J Clin Oncol. 2005 Nov 10;23(32):8253-61
references.pmid: 16278481
references.citation: Nat Rev Cancer. 2006 Aug;6(8):593-602
references.pmid: 16862190
references.citation: Cancer Res. 2007 Jan 15;67(2):528-36
references.pmid: 17234760
references.citation: J Biol Chem. 2003 Sep 5;278(36):34226-36
references.pmid: 12815063
references.citation: J Dent Res. 2005 Feb;84(2):160-5
references.pmid: 15668334
references.citation: Cancer Res. 2008 Jan 15;68(2):444-9
references.pmid: 18199538
references.citation: Cell Res. 2005 Jan;15(1):28-32
references.pmid: 15686623
references.citation: Cancer Cell. 2003 Sep;4(3):209-21
references.pmid: 14522255
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Cancer Cell. 2003 Jun;3(6):537-49
references.pmid: 12842083
references.citation: Cell. 2001 Mar 9;104(5):719-30
references.pmid: 11257226
references.citation: Oncogene. 1999 May 6;18(18):2883-91
references.pmid: 10362259
references.citation: Nature. 2007 Dec 6;450(7171):893-8
references.pmid: 17982442
references.citation: Dev Biol. 2003 Sep 1;261(1):39-54
references.pmid: 12941620
references.citation: Cancer Res. 2005 Nov 15;65(22):10423-30
references.pmid: 16288033
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D277-80
references.pmid: 14681412
references.citation: Cancer Res. 1999 Sep 1;59(17):4291-6
references.pmid: 10485474
references.citation: Mod Pathol. 2004 Mar;17(3):360-79
references.pmid: 14739906
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Dev Biol. 2008 Apr 15;316(2):302-11
references.pmid: 18325490
references.citation: Arch Histol Cytol. 2004 Dec;67(5):417-34
references.pmid: 15781983