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 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 2950 GSTP1; glutathione S-transferase pi 1 [KO:K23790] [EC:2.5.1.18] 1027 CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624] 1017 CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:2.7.11.22] 898 CCNE1; cyclin E1 [KO:K06626] 9134 CCNE2; cyclin E2 [KO:K06626] 5925 RB1; RB transcriptional corepressor 1 [KO:K06618] 1869 E2F1; E2F transcription factor 1 [KO:K17454] 1870 E2F2; E2F transcription factor 2 [KO:K09389] 1871 E2F3; E2F transcription factor 3 [KO:K06620] 7113 TMPRSS2; transmembrane serine protease 2 [KO:K09633] [EC:3.4.21.122] 2078 ERG; ETS transcription factor ERG [KO:K09435] 5328 PLAU; plasminogen activator, urokinase [KO:K01348] [EC:3.4.21.73] 5327 PLAT; plasminogen activator, tissue type [KO:K01343] [EC:3.4.21.68] 4314 MMP3; matrix metallopeptidase 3 [KO:K01394] [EC:3.4.24.17] 4318 MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35] 6935 ZEB1; zinc finger E-box binding homeobox 1 [KO:K09299] 7850 IL1R2; interleukin 1 receptor type 2 [KO:K04387] 6692 SPINT1; serine peptidase inhibitor, Kunitz type 1 [KO:K15619] 2119 ETV5; ETS variant transcription factor 5 [KO:K15593] 3630 INS; insulin [KO:K04526] 5154 PDGFA; platelet derived growth factor subunit A [KO:K04359] 5155 PDGFB; platelet derived growth factor subunit B [KO:K17386] 56034 PDGFC; platelet derived growth factor C [KO:K05450] 80310 PDGFD; platelet derived growth factor D [KO:K05450] 1950 EGF; epidermal growth factor [KO:K04357] 7039 TGFA; transforming growth factor alpha [KO:K08774] 3479 IGF1; insulin like growth factor 1 [KO:K05459] 3645 INSRR; insulin receptor related receptor [KO:K05086] [EC:2.7.10.1] 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] 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] 1956 EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1] 2064 ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1] 3480 IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1] 5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [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] 5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [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] 8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649] 5728 PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67] 5170 PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1] 4824 NKX3-1; NK3 homeobox 1 [KO:K09348] 207 AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1] 208 AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1] 10000 AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1] 842 CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62] 572 BAD; BCL2 associated agonist of cell death [KO:K02158] 2308 FOXO1; forkhead box O1 [KO:K07201] 1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625] 4193 MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27] 7157 TP53; tumor protein p53 [KO:K04451] 2932 GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26] 1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870] 468 ATF4; activating transcription factor 4 [KO:K04374] 10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048] 90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048] 64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048] 84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048] 148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048] 9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047] 1499 CTNNB1; catenin beta 1 [KO:K02105] 1387 CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48] 2033 EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48] 6932 TCF7; transcription factor 7 [KO:K02620] 83439 TCF7L1; transcription factor 7 like 1 [KO:K04490] 6934 TCF7L2; transcription factor 7 like 2 [KO:K04491] 51176 LEF1; lymphoid enhancer binding factor 1 [KO:K04492] 595 CCND1; cyclin D1 [KO:K04503] 1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10] 3551 IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10] 8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210] 4792 NFKBIA; NFKB inhibitor alpha [KO:K04734] 4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580] 5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735] 596 BCL2; BCL2 apoptosis regulator [KO:K02161] 2475 MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1] 2885 GRB2; growth factor receptor bound protein 2 [KO:K04364] 6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099] 6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099] 3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833] 3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827] 4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828] 369 ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1] 673 BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1] 5894 RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1] 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] 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] 6716 SRD5A2; steroid 5 alpha-reductase 2 [KO:K12344] [EC:1.3.1.22] 367 AR; androgen receptor [KO:K08557] 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] 7184 HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487] 354 KLK3; kallikrein related peptidase 3 [KO:K01351] [EC:3.4.21.77] 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. 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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 ///