ENTRY hsa05215 Pathway NAME Prostate cancer - Homo sapiens (human) DESCRIPTION Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer. CLASS Human Diseases; Cancer: specific types PATHWAY_MAP hsa05215 Prostate cancer NETWORK nt06214 PI3K signaling (cancer) nt06227 Nuclear receptor signaling (cancer) nt06230 Cell cycle (cancer) nt06263 Hepatocellular carcinoma nt06267 Small cell lung cancer nt06268 Melanoma nt06270 Breast cancer nt06271 Endometrial cancer nt06272 Prostate cancer nt06273 Glioma ELEMENT N00052 Mutation-inactivated PTEN to PI3K signaling pathway N00082 Loss of NKX3-1 to PI3K signaling pathway N00084 Amplified AR to androgen receptor signaling pathway N00085 Mutation-activated AR to androgen receptor signaling pathway N00093 Loss of CDKN1B to p27-cell cycle G1/S DISEASE H00024 Prostate cancer DRUG D00586 Flutamide (JP18/USP/INN) D00961 Bicalutamide (JP18/USP/INN) D00965 Nilutamide (USAN/INN) D01299 Chlormadinone acetate (JP18/USAN) D10218 Enzalutamide (JAN/USAN) D11040 Apalutamide (JAN/INN) D11045 Darolutamide (JAN/USAN/INN) ORGANISM Homo sapiens (human) [GN:hsa] GENE 10000 AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1] 1017 CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:2.7.11.22] 1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625] 1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624] 10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048] 110117499 P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649] 1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10] 1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870] 1387 CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48] 148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048] 1499 CTNNB1; catenin beta 1 [KO:K02105] 1869 E2F1; E2F transcription factor 1 [KO:K17454] 1870 E2F2; E2F transcription factor 2 [KO:K09389] 1871 E2F3; E2F transcription factor 3 [KO:K06620] 1950 EGF; epidermal growth factor [KO:K04357] 1956 EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1] 2033 EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48] 2064 ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1] 207 AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1] 2078 ERG; ETS transcription factor ERG [KO:K09435] 208 AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1] 2119 ETV5; ETS variant transcription factor 5 [KO:K15593] 2260 FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:2.7.10.1] 2263 FGFR2; fibroblast growth factor receptor 2 [KO:K05093] [EC:2.7.10.1] 2308 FOXO1; forkhead box O1 [KO:K07201] 2475 MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1] 2885 GRB2; growth factor receptor bound protein 2 [KO:K04364] 2932 GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26] 2950 GSTP1; glutathione S-transferase pi 1 [KO:K23790] 3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833] 3320 HSP90AA1; heat shock protein 90 alpha family class A member 1 [KO:K04079] 3326 HSP90AB1; heat shock protein 90 alpha family class B member 1 [KO:K04079] 3479 IGF1; insulin like growth factor 1 [KO:K05459] 3480 IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1] 354 KLK3; kallikrein related peptidase 3 [KO:K01351] [EC:3.4.21.77] 3551 IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10] 3630 INS; insulin [KO:K04526] 3645 INSRR; insulin receptor related receptor [KO:K05086] [EC:2.7.10.1] 367 AR; androgen receptor [KO:K08557] 369 ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1] 3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827] 4193 MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27] 4314 MMP3; matrix metallopeptidase 3 [KO:K01394] [EC:3.4.24.17] 4318 MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35] 468 ATF4; activating transcription factor 4 [KO:K04374] 4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580] 4792 NFKBIA; NFKB inhibitor alpha [KO:K04734] 4824 NKX3-1; NK3 homeobox 1 [KO:K09348] 4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828] 51176 LEF1; lymphoid enhancer binding factor 1 [KO:K04492] 5154 PDGFA; platelet derived growth factor subunit A [KO:K04359] 5155 PDGFB; platelet derived growth factor subunit B [KO:K17386] 5156 PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1] 5159 PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1] 5170 PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1] 5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153] 5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153] 5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153] 5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649] 5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649] 5327 PLAT; plasminogen activator, tissue type [KO:K01343] [EC:3.4.21.68] 5328 PLAU; plasminogen activator, urokinase [KO:K01348] [EC:3.4.21.73] 5594 MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24] 5595 MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24] 56034 PDGFC; platelet derived growth factor C [KO:K05450] 5604 MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2] 5605 MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2] 572 BAD; BCL2 associated agonist of cell death [KO:K02158] 5728 PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67] 5894 RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1] 5925 RB1; RB transcriptional corepressor 1 [KO:K06618] 595 CCND1; cyclin D1 [KO:K04503] 596 BCL2; BCL2 apoptosis regulator [KO:K02161] 5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735] 64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048] 6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099] 6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099] 6692 SPINT1; serine peptidase inhibitor, Kunitz type 1 [KO:K15619] 6716 SRD5A2; steroid 5 alpha-reductase 2 [KO:K12344] [EC:1.3.1.22] 673 BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1] 6932 TCF7; transcription factor 7 [KO:K02620] 6934 TCF7L2; transcription factor 7 like 2 [KO:K04491] 6935 ZEB1; zinc finger E-box binding homeobox 1 [KO:K09299] 7039 TGFA; transforming growth factor alpha [KO:K08774] 7113 TMPRSS2; transmembrane serine protease 2 [KO:K09633] [EC:3.4.21.122] 7157 TP53; tumor protein p53 [KO:K04451] 7184 HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487] 7850 IL1R2; interleukin 1 receptor type 2 [KO:K04387] 80310 PDGFD; platelet derived growth factor D [KO:K05450] 83439 TCF7L1; transcription factor 7 like 1 [KO:K04490] 842 CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62] 84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048] 8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649] 8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210] 898 CCNE1; cyclin E1 [KO:K06626] 90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048] 9134 CCNE2; cyclin E2 [KO:K06626] 9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047] COMPOUND C00280 Androstenedione C00410 Progesterone C00535 Testosterone C00735 Cortisol C00762 Cortisone C00951 Estradiol-17beta C01227 Dehydroepiandrosterone C03917 Dihydrotestosterone C05981 Phosphatidylinositol-3,4,5-trisphosphate C07653 Flutamide C16038 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine REFERENCE PMID:12878745 AUTHORS Nelson WG, De Marzo AM, Isaacs WB. TITLE Prostate cancer. JOURNAL N Engl J Med 349:366-81 (2003) DOI:10.1056/NEJMra021562 REFERENCE PMID:15724144 AUTHORS Li L, Ittmann MM, Ayala G, Tsai MJ, Amato RJ, Wheeler TM, Miles BJ, Kadmon D, Thompson TC. TITLE The emerging role of the PI3-K-Akt pathway in prostate cancer progression. JOURNAL Prostate Cancer Prostatic Dis 8:108-18 (2005) DOI:10.1038/sj.pcan.4500776 REFERENCE PMID:16551847 AUTHORS Pienta KJ, Bradley D. TITLE Mechanisms underlying the development of androgen-independent prostate cancer. JOURNAL Clin Cancer Res 12:1665-71 (2006) DOI:10.1158/1078-0432.CCR-06-0067 REFERENCE PMID:11900250 AUTHORS Feldman BJ, Feldman D. TITLE The development of androgen-independent prostate cancer. JOURNAL Nat Rev Cancer 1:34-45 (2001) DOI:10.1038/35094009 REFERENCE PMID:15082523 AUTHORS Heinlein CA, Chang C. TITLE Androgen receptor in prostate cancer. JOURNAL Endocr Rev 25:276-308 (2004) DOI:10.1210/er.2002-0032 REFERENCE PMID:9422516 AUTHORS Koivisto P, Kolmer M, Visakorpi T, Kallioniemi OP. TITLE Androgen receptor gene and hormonal therapy failure of prostate cancer. JOURNAL Am J Pathol 152:1-9 (1998) REFERENCE PMID:10835690 AUTHORS Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, Feldman D. TITLE Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. JOURNAL Nat Med 6:703-6 (2000) DOI:10.1038/76287 REFERENCE PMID:10453277 AUTHORS Macri E, Loda M. TITLE Role of p27 in prostate carcinogenesis. JOURNAL Cancer Metastasis Rev 17:337-44 (1998) DOI:10.1023/A:1006133620914 REFERENCE PMID:11750244 AUTHORS Steers WD. TITLE 5alpha-reductase activity in the prostate. JOURNAL Urology 58:17-24; discussion 24 (2001) DOI:10.1016/S0090-4295(01)01299-7 REFERENCE PMID:8069858 AUTHORS Lin D, Meyer DJ, Ketterer B, Lang NP, Kadlubar FF. TITLE Effects of human and rat glutathione S-transferases on the covalent DNA binding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro: a possible mechanism of organ specificity in their carcinogenesis. JOURNAL Cancer Res 54:4920-6 (1994) REFERENCE PMID:11527574 AUTHORS Grimes CA, Jope RS. TITLE The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. JOURNAL Prog Neurobiol 65:391-426 (2001) DOI:10.1016/S0301-0082(01)00011-9 REFERENCE PMID:21747944 AUTHORS Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, Cohen Y, Jacob-Hirsch J, Ehrlich M, Ben-Sasson S, Goldfinger N, Loewenthal R, Gazit E, Rotter V, Berger R TITLE TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. JOURNAL PLoS One 6:e21650 (2011) DOI:10.1371/journal.pone.0021650 REFERENCE PMID:20478527 AUTHORS Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM TITLE An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. JOURNAL Cancer Cell 17:443-54 (2010) DOI:10.1016/j.ccr.2010.03.018 REFERENCE PMID:19399032 AUTHORS Squire JA TITLE TMPRSS2-ERG and PTEN loss in prostate cancer. JOURNAL Nat Genet 41:509-10 (2009) DOI:10.1038/ng0509-509 REFERENCE PMID:25915839 AUTHORS Adamo P, Ladomery MR TITLE The oncogene ERG: a key factor in prostate cancer. JOURNAL Oncogene 35:403-14 (2016) DOI:10.1038/onc.2015.109 REFERENCE PMID:25485532 AUTHORS Burdova A, Bouchal J, Tavandzis S, Kolar Z TITLE TMPRSS2-ERG gene fusion in prostate cancer. JOURNAL Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 158:502-10 (2014) DOI:10.5507/bp.2014.065 REFERENCE PMID:18172298 AUTHORS Helgeson BE, Tomlins SA, Shah N, Laxman B, Cao Q, Prensner JR, Cao X, Singla N, Montie JE, Varambally S, Mehra R, Chinnaiyan AM TITLE Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. JOURNAL Cancer Res 68:73-80 (2008) DOI:10.1158/0008-5472.CAN-07-5352 REFERENCE PMID:28968951 AUTHORS Kim H, Datta A, Talwar S, Saleem SN, Mondal D, Abdel-Mageed AB TITLE Estradiol-ERbeta2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion. JOURNAL Oncotarget 8:62820-62833 (2017) DOI:10.18632/oncotarget.11355 REL_PATHWAY hsa00140 Steroid hormone biosynthesis hsa04010 MAPK signaling pathway hsa04060 Cytokine-cytokine receptor interaction hsa04110 Cell cycle hsa04115 p53 signaling pathway hsa04151 PI3K-Akt signaling pathway hsa04210 Apoptosis hsa05202 Transcriptional misregulation in cancer KO_PATHWAY ko05215 ///