Molecular and cellular mechanisms of castration resistant prostate cancer (Review)

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI

Society AC: Cancer facts & figures 2016. Atlanta: American Cancer Society; 2016

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al: Integrative genomic profiling of human prostate cancer. Cancer Cell. 18:11–22. 2010. View Article : Google Scholar : PubMed/NCBI

Thomas C, Bögemann M, König F, Machtens S, Schostak M, Steuber T and Heidenreich A: Advanced prostate cancer consensus conference (APCCC) 2015 in St. Gallen. Critical review of the recommendations on diagnosis and therapy of metastatic prostate cancer by a German expert panel. Urologe A. 55:772–782. 2016.(In German).

Ozono S and Furuse H: Progress of the treatment for CRPC. Nihon Rinsho. 74 Suppl 3:S615–S618. 2016.(In Japanese).

Lian F, Sharma NV, Moran JD and Moreno CS: The biology of castration-resistant prostate cancer. Curr Probl Cancer. 39:17–28. 2015. View Article : Google Scholar : PubMed/NCBI

Maughan BL and Antonarakis ES: Androgen pathway resistance in prostate cancer and therapeutic implications. Expert Opin Pharmacother. 16:1521–1537. 2015. View Article : Google Scholar : PubMed/NCBI

Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS and Chatterjee B: Androgen receptor: Structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci. 949:44–57. 2001. View Article : Google Scholar : PubMed/NCBI

Gelmann EP: Molecular biology of the androgen receptor. J Clin Oncol. 20:3001–3015. 2002. View Article : Google Scholar : PubMed/NCBI

Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Bañuelos CA, et al: Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell. 17:535–546. 2010. View Article : Google Scholar : PubMed/NCBI

Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, Gjyrezi A, Chanel-Vos C, Shen R, Tagawa ST, et al: Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res. 71:6019–6029. 2011. View Article : Google Scholar : PubMed/NCBI

Aggarwal RR, Thomas G, Youngren J, Foye A, Olson S, Paris P, Beer TM, Ryan CJ, Witte O, Evans CP, et al: Androgen receptor (AR) amplification in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) and enzalutamide (Enz): Preliminary results from the SU2C/PCF/AACR West Coast prostate cancer dream team (WCDT). J Clin Oncol. 33:50682015.

Haapala K, Kuukasjärvi T, Hyytinen E, Rantala I, Helin HJ and Koivisto PA: Androgen receptor amplification is associated with increased cell proliferation in prostate cancer. Hum Pathol. 38:474–478. 2007. View Article : Google Scholar : PubMed/NCBI

Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, Levink R, Coumans F, Moreira J, Riisnaes R, et al: Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 69:2912–2918. 2009. View Article : Google Scholar : PubMed/NCBI

Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, Willi N, Mihatsch MJ, Sauter G and Kallioniemi OP: Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res. 59:803–806. 1999.PubMed/NCBI

Linja MJ, Savinainen KJ, Saramäki OR, Tammela TL, Vessella RL and Visakorpi T: Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 61:3550–3555. 2001.PubMed/NCBI

Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG and Sawyers CL: Molecular determinants of resistance to antiandrogen therapy. Nat Med. 10:33–39. 2004. View Article : Google Scholar : PubMed/NCBI

Kim D, Gregory CW, French FS, Smith GJ and Mohler JL: Androgen receptor expression and cellular proliferation during transition from androgen-dependent to recurrent growth after castration in the CWR22 prostate cancer xenograft. Am J Pathol. 160:219–226. 2002. View Article : Google Scholar : PubMed/NCBI

Santer FR, Erb HH and McNeill RV: Therapy escape mechanisms in the malignant prostate. Seminars Cancer Biol. 35:133–144. 2015. View Article : Google Scholar

Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ, Jänne OA and Visakorpi T: Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 69:8141–8149. 2009. View Article : Google Scholar : PubMed/NCBI

Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T and Kallioniemi OP: Androgen receptor gene amplification: A possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 57:314–319. 1997.PubMed/NCBI

Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, White TA, Stojanov P, Van Allen E, Stransky N, et al: Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 44:685–689. 2012. View Article : Google Scholar : PubMed/NCBI

Mayeur GL, Kung WJ, Martinez A, Izumiya C, Chen DJ and Kung HJ: Ku is a novel transcriptional recycling coactivator of the androgen receptor in prostate cancer cells. J Biol Chem. 280:10827–10833. 2005. View Article : Google Scholar : PubMed/NCBI

Sarkar S, Brautigan DL, Parsons SJ and Larner JM: Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene. 33:26–33. 2014. View Article : Google Scholar : PubMed/NCBI

Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E, van Rooij HC, Trapman J, Brinkmann AO and Mulder E: A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 173:534–540. 1990. View Article : Google Scholar : PubMed/NCBI

Gaddipati JP, McLeod DG, Heidenberg HB, Sesterhenn IA, Finger MJ, Moul JW and Srivastava S: Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res. 54:2861–2864. 1994.PubMed/NCBI

Suzuki H, Sato N, Watabe Y, Masai M, Seino S and Shimazaki J: Androgen receptor gene mutations in human prostate cancer. J Steroid Biochem Mol Biol. 46:759–765. 1993. View Article : Google Scholar : PubMed/NCBI

Suzuki H, Akakura K, Komiya A, Aida S, Akimoto S and Shimazaki J: Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: Relation to antiandrogen withdrawal syndrome. Prostate. 29:153–158. 1996. View Article : Google Scholar : PubMed/NCBI

Steketee K, Timmerman L, Ziel-van der Made AC, Doesburg P, Brinkmann AO and Trapman J: Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer. Int J Cancer. 100:309–317. 2002. View Article : Google Scholar : PubMed/NCBI

Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, Arora VK, Watson PA, Chen Y, Greene GL, Shen Y and Sawyers CL: Overcoming mutation-based resistance to antiandrogens with rational drug design. Elife. 2:e004992013. View Article : Google Scholar : PubMed/NCBI

Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, et al: Integrative clinical genomics of advanced prostate cancer. Cell. 161:1215–1228. 2015. View Article : Google Scholar : PubMed/NCBI

Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, Anderson SA, McConeghy B, Shukin R, Bazov J, et al: Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 21:2315–2324. 2015. View Article : Google Scholar : PubMed/NCBI

Alliance for Clinical Trials in Oncology, . Enzalutamide with or without abiraterone and prednisone in treating patients with castration-resistant metastatic prostate cancer. ClinicalTrials.gov Identifier: NCT01949337. https://clinicaltrials.gov/ct2/show/NCT01949337September 24–2013

Nakazawa M, Antonarakis ES and Luo J: Androgen receptor splice variants in the era of enzalutamide and abiraterone. Horm Cancer. 5:265–273. 2014. View Article : Google Scholar : PubMed/NCBI

Haile S and Sadar MD: Androgen receptor and its splice variants in prostate cancer. Cell Mol Life Sci. 68:3971–3981. 2011. View Article : Google Scholar : PubMed/NCBI

Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, et al: Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69:16–22. 2009. View Article : Google Scholar : PubMed/NCBI

Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, et al: A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69:2305–2313. 2009. View Article : Google Scholar : PubMed/NCBI

Dehm SM, Schmidt LJ, Heemers HV, Vessella RL and Tindall DJ: Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68:5469–5477. 2008. View Article : Google Scholar : PubMed/NCBI

Fenner A: Prostate cancer: Unravelling AR splice variant signalling in CPRC. Nat Rev Urol. 9:4102012. View Article : Google Scholar : PubMed/NCBI

Ware KE, Garcia-Blanco MA, Armstrong AJ and Dehm SM: Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer. Endocr Relat Cancer. 21:T87–T103. 2014. View Article : Google Scholar : PubMed/NCBI

Penel N: Splicing variant of androgen receptors (AR-V7): New paradigms. Bull Cancer. 103:711–713. 2016.(In French). View Article : Google Scholar : PubMed/NCBI

Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, Yang X, Zhang H, Zhu Y and Shi G: Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 5:76542015. View Article : Google Scholar : PubMed/NCBI

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 371:1028–1038. 2014. View Article : Google Scholar : PubMed/NCBI

Zhan Y, Zhang G, Wang X, Qi Y, Bai S, Li D, Ma T, Sartor O, Flemington EK, Zhang H, et al: Interplay between cytoplasmic and nuclear androgen receptor splice variants mediates castration resistance. Mol Cancer Res. 15:59–68. 2017. View Article : Google Scholar : PubMed/NCBI

Yang YC, Mawji N, Wang J and Sadar M: Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer. Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, San Diego, CA, 2014. Cancer Res. 74(Suppl 19): Abstract 610. 2014;

Ito Y, Banuelos CA and Sadar MD: Combination therapy with EPI-002 and parp inhibitor for castration-resistant prostate cancer. J Urol. 197:E11082017. View Article : Google Scholar

Hermanson O, Glass CK and Rosenfeld MG: Nuclear receptor coregulators: Multiple modes of modification. Trends Endocrinol Metab. 13:55–60. 2002. View Article : Google Scholar : PubMed/NCBI

Culig Z: Androgen receptor coactivators in regulation of growth and differentiation in prostate cancer. J Cell Physiol. 231:270–274. 2016. View Article : Google Scholar : PubMed/NCBI

Wolf IM, Heitzer MD, Grubisha M and DeFranco DB: Coactivators and nuclear receptor transactivation. J Cell Biochem. 104:1580–1586. 2008. View Article : Google Scholar : PubMed/NCBI

Massie CE, Adryan B, Barbosa-Morais NL, Lynch AG, Tran MG, Neal DE and Mills IG: New androgen receptor genomic targets show an interaction with the ETS1 transcription factor. EMBO Rep. 8:871–878. 2007. View Article : Google Scholar : PubMed/NCBI

Bennett NC, Gardiner RA, Hooper JD, Johnson DW and Gobe GC: Molecular cell biology of androgen receptor signalling. Int J Biochem Cell Biol. 42:813–827. 2010. View Article : Google Scholar : PubMed/NCBI

Zhang Z, Chang CW, Goh WL, Sung WK and Cheung E: CENTDIST: Discovery of co-associated factors by motif distribution. Nucleic Acids Res. 39(Web Server issue): W391–W399. 2011. View Article : Google Scholar : PubMed/NCBI

Wang Q, Li W, Liu XS, Carroll JS, Jänne OA, Keeton EK, Chinnaiyan AM, Pienta KJ and Brown M: A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell. 27:380–392. 2007. View Article : Google Scholar : PubMed/NCBI

Tan PY, Chang CW, Chng KR, Wansa KD, Sung WK and Cheung E: Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival. Mol Cell Biol. 32:399–414. 2012. View Article : Google Scholar : PubMed/NCBI

Heemers HV and Tindall DJ: Androgen receptor (AR) coregulators: A diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 28:778–808. 2007. View Article : Google Scholar : PubMed/NCBI

Ni L, Yang CS, Gioeli D, Frierson H, Toft DO and Paschal BM: FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 30:1243–1253. 2010. View Article : Google Scholar : PubMed/NCBI

Chen S, Sullivan WP, Toft DO and Smith DF: Differential interactions of p23 and the TPR-containing proteins Hop, Cyp40, FKBP52 and FKBP51 with Hsp90 mutants. Cell Stress Chaperones. 3:118–129. 1998. View Article : Google Scholar : PubMed/NCBI

Wissmann M, Yin N, Müller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Günther T, Buettner R, et al: Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol. 9:347–353. 2007. View Article : Google Scholar : PubMed/NCBI

Laschak M, Bechtel M, Spindler KD and Hessenauer A: Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines. Int J Mol Med. 28:645–651. 2011.PubMed/NCBI

Zaret KS and Carroll JS: Pioneer transcription factors: Establishing competence for gene expression. Genes Dev. 25:2227–2241. 2011. View Article : Google Scholar : PubMed/NCBI

Coffey K and Robson CN: Regulation of the androgen receptor by post-translational modifications. J Endocrinol. 215:221–237. 2012. View Article : Google Scholar : PubMed/NCBI

Chen MF, Chen WC, Chang YJ, Wu CF and Wu CT: Role of DNA methyltransferase 1 in hormone-resistant prostate cancer. J Mol Med (Berl). 88:953–962. 2010. View Article : Google Scholar : PubMed/NCBI

Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS and Whang YE: Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 29:3208–3216. 2010. View Article : Google Scholar : PubMed/NCBI

Willder JM, Heng SJ, McCall P, Adams CE, Tannahill C, Fyffe G, Seywright M, Horgan PG, Leung HY, Underwood MA and Edwards J: Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients. Br J Cancer. 108:139–148. 2013. View Article : Google Scholar : PubMed/NCBI

Ha S, Iqbal NJ, Mita P, Ruoff R, Gerald WL, Lepor H, Taneja SS, Lee P, Melamed J, Garabedian MJ and Logan SK: Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. Oncogene. 32:3992–4000. 2013. View Article : Google Scholar : PubMed/NCBI

Shu SK, Liu Q, Coppola D and Cheng JQ: Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem. 285:33045–33053. 2010. View Article : Google Scholar : PubMed/NCBI

Xia Y, Wang M, Beraldi E, Cong M, Zoubeidi A, Gleave M and Peng L: A novel triazole nucleoside suppresses prostate cancer cell growth by inhibiting heat shock factor 1 and androgen receptor. Anticancer Agents Med Chem. 15:1333–1340. 2015. View Article : Google Scholar : PubMed/NCBI

Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, et al: Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1:487–495. 2011. View Article : Google Scholar : PubMed/NCBI

Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, Warren A, Scott H, Madhu B, Sharma N, et al: The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 30:2719–2733. 2011. View Article : Google Scholar : PubMed/NCBI

Kumagai J, Hofland J, Erkens-Schulze S, Dits NFJ, Jenster G, Bangma CH, Homma Y, De Jong FH and Van Weerden WM: Intratumoral conversion of adrenal androgens is more important than De Novo intratumoral steroid synthesis in prostate cancer. Eur Urol Suppl. 10:2642011. View Article : Google Scholar

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD and Nelson PS: Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res. 68:4447–4454. 2008. View Article : Google Scholar : PubMed/NCBI

Yin L and Hu Q: CYP17 inhibitors-abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nat Rev Urol. 11:32–42. 2014. View Article : Google Scholar : PubMed/NCBI

Knuuttila M, Yatkin E, Kallio J, Savolainen S, Laajala TD, Aittokallio T, Oksala R, Häkkinen M, Keski-Rahkonen P, Auriola S, et al: Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. Am J Pathol. 184:2163–2173. 2014. View Article : Google Scholar : PubMed/NCBI

Tamae D, Mostaghel E, Montgomery B, Nelson PS, Balk SP, Kantoff PW, Taplin ME and Penning TM: The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Interact. 234:332–338. 2015. View Article : Google Scholar : PubMed/NCBI

Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 368:138–148. 2013. View Article : Google Scholar : PubMed/NCBI

Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 371:424–433. 2014. View Article : Google Scholar : PubMed/NCBI

Chandrasekar T, Yang JC, Gao AC and Evans CP: Targeting molecular resistance in castration-resistant prostate cancer. BMC Med. 13:2062015. View Article : Google Scholar : PubMed/NCBI

Wang BH: Molecular mechanisms of gene regulation mediated by nuclear receptor superfamily. Sheng Li Ke Xue Jin Zhan. 34:369–372. 2003.(In Chinese). PubMed/NCBI

Laudet V, Hänni C, Coll J, Catzeflis F and Stéhelin D: Evolution of the nuclear receptor gene superfamily. EMBO J. 11:1003–1013. 1992.PubMed/NCBI

Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A, Zagaja GP, Brendler CB, Stadler WM and Conzen SD: Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. Prostate. 72:157–164. 2012. View Article : Google Scholar : PubMed/NCBI

Sahu B, Laakso M, Pihlajamaa P, Ovaska K, Sinielnikov I, Hautaniemi S and Jänne OA: FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res. 73:1570–1580. 2013. View Article : Google Scholar : PubMed/NCBI

Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, et al: Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 155:1309–1322. 2013. View Article : Google Scholar : PubMed/NCBI

Montgomery B, Cheng HH, Drechsler J and Mostaghel EA: Glucocorticoids and prostate cancer treatment: Friend or foe? Asian J Androl. 16:354–358. 2014. View Article : Google Scholar : PubMed/NCBI

Montgomery B, Kheoh T, Molina A, Li J, Bellmunt J, Tran N, Loriot Y, Efstathiou E, Ryan CJ, Scher HI and de Bono JS: Impact of baseline corticosteroids on survival and steroid androgens in metastatic castration-resistant prostate cancer: Exploratory analysis from COU-AA-301. Eur Urol. 67:866–873. 2015. View Article : Google Scholar : PubMed/NCBI

Song C, Kim Y, Min GE and Ahn H: Dihydrotestosterone enhances castration-resistant prostate cancer cell proliferation through STAT5 activation via glucocorticoid receptor pathway. Prostate. 74:1240–1248. 2014. View Article : Google Scholar : PubMed/NCBI

Lorente D, Omlin A, Ferraldeschi R, Pezaro C, Perez R, Mateo J, Altavilla A, Zafeirou Z, Tunariu N, Parker C, et al: Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. Br J Cancer. 111:2248–2253. 2014. View Article : Google Scholar : PubMed/NCBI

Chen R, Yu Y and Dong X: Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer. J Steroid Biochem Mol Biol. 166:91–96. 2017. View Article : Google Scholar : PubMed/NCBI

Grindstad T, Andersen S, Al-Saad S, Donnem T, Kiselev Y, Nordahl Melbø-Jørgensen C, Skjefstad K, Busund LT, Bremnes RM and Richardsen E: High progesterone receptor expression in prostate cancer is associated with clinical failure. PloS One. 10:e01166912015. View Article : Google Scholar : PubMed/NCBI

Morgensztern D and McLeod HL: PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs. 16:797–803. 2005. View Article : Google Scholar : PubMed/NCBI

Statz CM, Patterson SE and Mockus SM: mTOR inhibitors in castration-resistant prostate cancer: A systematic review. Target Oncol. 12:47–59. 2017. View Article : Google Scholar : PubMed/NCBI

Kato M, Banuelos CA, Imamura Y, Leung JK, Caley DP, Wang J, Mawji NR and Sadar MD: Cotargeting androgen receptor splice variants and mTOR signaling pathway for the treatment of castration-resistant prostate cancer. Clin Cancer Res. 22:2744–2754. 2016. View Article : Google Scholar : PubMed/NCBI

McMenamin ME, Soung P, Perera S, Kaplan I, Loda M and Sellers WR: Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 59:4291–4296. 1999.PubMed/NCBI

Zhang W, Zhu J, Efferson CL, Ware C, Tammam J, Angagaw M, Laskey J, Bettano KA, Kasibhatla S, Reilly JF, et al: Inhibition of tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-deficient mouse model of prostate cancer. Cancer Res. 69:7466–7472. 2009. View Article : Google Scholar : PubMed/NCBI

Park SI, Shah AN, Zhang J and Gallick GE: Regulation of angiogenesis and vascular permeability by Src family kinases: Opportunities for therapeutic treatment of solid tumors. Expert Opin Ther Targets. 11:1207–1217. 2007. View Article : Google Scholar : PubMed/NCBI

Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, et al: Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): A randomised, double-blind phase 3 trial. Lancet Oncol. 14:1307–1316. 2013. View Article : Google Scholar : PubMed/NCBI

Yang JC, Bai L, Yap S, Gao AC, Kung HJ and Evans CP: Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol Cancer Ther. 9:1629–1637. 2010. View Article : Google Scholar : PubMed/NCBI

Bettedi L and Foukas LC: Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing. Biogerontology. 18:913–929. 2017. View Article : Google Scholar : PubMed/NCBI

Neto AS, Tobias-Machado M, Wroclawski ML, Fonseca FL, Pompeo AC and Del Giglio A: Molecular oncogenesis of prostate adenocarcinoma: Role of the human epidermal growth factor receptor 2 (HER-2/neu). Tumori. 96:645–649. 2010. View Article : Google Scholar : PubMed/NCBI

Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH and Hung MC: HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 60:6841–6845. 2000.PubMed/NCBI

Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, et al: Cabozantinib in patients with advanced prostate cancer: Results of a phase II randomized discontinuation trial. J Clin Oncol. 31:412–419. 2013. View Article : Google Scholar : PubMed/NCBI

Cannistraci A, Di Pace AL, De Maria R and Bonci D: MicroRNA as new tools for prostate cancer risk assessment and therapeutic intervention: Results from clinical data set and patients' samples. Biomed Res Int. 2014:1461702014. View Article : Google Scholar : PubMed/NCBI

Kojima S, Goto Y and Naya Y: The roles of microRNAs in the progression of castration-resistant prostate cancer. J Hum Genet. 62:25–31. 2017. View Article : Google Scholar : PubMed/NCBI

Cannistraci A, Di Pace AL, Di Pace AL, De Maria R and Bonci D: MicroRNA as new tools for prostate cancer risk assessment and therapeutic intervention: Results from clinical data set and patients' samples. Biomed Res Int. 2014:1461702014. View Article : Google Scholar : PubMed/NCBI

Schaefer A, Jung M, Mollenkopf HJ, Wagner I, Stephan C, Jentzmik F, Miller K, Lein M, Kristiansen G and Jung K: Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 126:1166–1176. 2010.PubMed/NCBI

Jalava SE, Urbanucci A, Latonen L, Waltering KK, Sahu B, Jänne OA, Seppälä J, Lähdesmäki H, Tammela TL and Visakorpi T: Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer. Oncogene. 31:4460–4471. 2012. View Article : Google Scholar : PubMed/NCBI

Takeshita F, Patrawala L, Osaki M, Takahashi RU, Yamamoto Y, Kosaka N, Kawamata M, Kelnar K, Bader AG, Brown D and Ochiya T: Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther. 18:181–187. 2010. View Article : Google Scholar : PubMed/NCBI

Kashat M, Azzouz L, Sarkar SH, Kong D, Li Y and Sarkar FH: Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness. Am J Transl Res. 4:432–442. 2012.PubMed/NCBI

Majid S, Dar AA, Saini S, Shahryari V, Arora S, Zaman MS, Chang I, Yamamura S, Tanaka Y, Chiyomaru T, et al: miRNA-34b inhibits prostate cancer through demethylation, active chromatin modifications, and AKT pathways. Clin Cancer Res. 19:73–84. 2013. View Article : Google Scholar : PubMed/NCBI

Barron N, Keenan J, Gammell P, Martinez VG, Freeman A, Masters JR and Clynes M: Biochemical relapse following radical prostatectomy and miR-200a levels in prostate cancer. Prostate. 72:1193–1199. 2012. View Article : Google Scholar : PubMed/NCBI

Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, et al: Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 322:1695–1699. 2008. View Article : Google Scholar : PubMed/NCBI

Mortensen MM, Høyer S, Orntoft TF, Sørensen KD, Dyrskjøt L and Borre M: High miR-449b expression in prostate cancer is associated with biochemical recurrence after radical prostatectomy. BMC Cancer. 14:8592014. View Article : Google Scholar : PubMed/NCBI

Casanova-Salas I, Rubio-Briones J, Calatrava A, Mancarella C, Masiá E, Casanova J, Fernández-Serra A, Rubio L, Ramírez-Backhaus M, Armiñán A, et al: Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J Urol. 192:252–259. 2014. View Article : Google Scholar : PubMed/NCBI

Nam RK, Benatar T, Wallis CJ, Amemiya Y, Yang W, Garbens A, Naeim M, Sherman C, Sugar L and Seth A: MiR-301a regulates E-cadherin expression and is predictive of prostate cancer recurrence. Prostate. 76:869–884. 2016. View Article : Google Scholar : PubMed/NCBI

Bell EH, Kirste S, Fleming JL, Stegmaier P, Drendel V, Mo X, Ling S, Fabian D, Manring I, Jilg CA, et al: A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy. PloS One. 10:e01187452015. View Article : Google Scholar : PubMed/NCBI

Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, Bhatia J, Stadler Z, Fine SW, Reuter V, et al: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 16:2115–2121. 2010. View Article : Google Scholar : PubMed/NCBI

Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY, Jarosz M, Lipson D, Tagawa ST, Nanus DM, et al: Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 63:920–926. 2013. View Article : Google Scholar : PubMed/NCBI

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, Mahmud N, Dadaev T, Govindasami K, Guy M, et al: Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 31:1748–1757. 2013. View Article : Google Scholar : PubMed/NCBI

Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H, Yu J, et al: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 19:664–678. 2011. View Article : Google Scholar : PubMed/NCBI

Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 373:1697–1708. 2015. View Article : Google Scholar : PubMed/NCBI

Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, Arora VK, Yen WF, Cai L, Zheng D, et al: Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 3:1245–1253. 2013. View Article : Google Scholar : PubMed/NCBI

Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, Ma T, Den RB, Dicker AP, Feng FY and Knudsen KE: A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 3:1254–1271. 2013. View Article : Google Scholar : PubMed/NCBI

Li L, Chang W, Yang G, Ren C, Park S, Karantanos T, Karanika S, Wang J, Yin J, Shah PK, et al: Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Sci Signal. 7:ra472014. View Article : Google Scholar : PubMed/NCBI

Farrow JM, Yang JC and Evans CP: Autophagy as a modulator and target in prostate cancer. Nat Rev Urol. 11:508–516. 2014. View Article : Google Scholar : PubMed/NCBI

Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, et al: Autophagy in malignant transformation and cancer progression. EMBO J. 34:856–880. 2015. View Article : Google Scholar : PubMed/NCBI

Jiang X, Zhong W, Huang H, He H, Jiang F, Chen Y, Yue F, Zou J, Li X, He Y, et al: Autophagy defects suggested by low levels of autophagy activator MAP1S and high levels of autophagy inhibitor LRPPRC predict poor prognosis of prostate cancer patients. Mol Carcinog. 54:1194–1204. 2015. View Article : Google Scholar : PubMed/NCBI

Jiang X, Li X, Huang H, Jiang F, Lin Z, He H, Chen Y, Yue F, Zou J, He Y, et al: Elevated levels of mitochondrion-associated autophagy inhibitor LRPPRC are associated with poor prognosis in patients with prostate cancer. Cancer. 120:1228–1236. 2014. View Article : Google Scholar : PubMed/NCBI

Mathew R, Karantza-Wadsworth V and White E: Role of autophagy in cancer. Nat Rev Cancer. 7:961–967. 2007. View Article : Google Scholar : PubMed/NCBI

Hönscheid P, Datta K and Muders MH: Autophagy: Detection, regulation and its role in cancer and therapy response. Int J Radiat Biol. 90:628–635. 2014. View Article : Google Scholar : PubMed/NCBI

Ziparo E, Petrungaro S, Marini ES, Starace D, Conti S, Facchiano A, Filippini A and Giampietri C: Autophagy in prostate cancer and androgen suppression therapy. Int J Mol Sci. 14:12090–12106. 2013. View Article : Google Scholar : PubMed/NCBI

Bennett HL, Stockley J, Fleming JT, Mandal R, O'Prey J, Ryan KM, Robson CN and Leung HY: Does androgen-ablation therapy (AAT) associated autophagy have a pro-survival effect in LNCaP human prostate cancer cells? BJU Int. 111:672–682. 2013. View Article : Google Scholar : PubMed/NCBI

Li M, Jiang X, Liu D, Na Y, Gao GF and Xi Z: Autophagy protects LNCaP cells under androgen deprivation conditions. Autophagy. 4:54–60. 2008. View Article : Google Scholar : PubMed/NCBI

Xu Y, Chen SY, Ross KN and Balk SP: Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 66:7783–7792. 2006. View Article : Google Scholar : PubMed/NCBI

Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S and Mak TW: Regulation of PTEN transcription by p53. Mol Cell. 8:317–325. 2001. View Article : Google Scholar : PubMed/NCBI

Colquhoun AJ, Venier NA, Vandersluis AD, Besla R, Sugar LM, Kiss A, Fleshner NE, Pollak M, Klotz LH and Venkateswaran V: Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 15:346–352. 2012. View Article : Google Scholar : PubMed/NCBI

Notte A, Ninane N, Arnould T and Michiels C: Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells: Role of autophagy and JNK activation. Cell Death Dis. 4:e6382013. View Article : Google Scholar : PubMed/NCBI

Li Y, Luo P, Wang J, Dai J, Yang X, Wu H, Yang B and He Q: Autophagy blockade sensitizes the anticancer activity of CA-4 via JNK-Bcl-2 pathway. Toxicol Appl Pharmacol. 274:319–327. 2014. View Article : Google Scholar : PubMed/NCBI

Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI

Maitland NJ, Frame FM, Polson ES, Lewis JL and Collins AT: Prostate cancer stem cells: Do they have a basal or luminal phenotype? Horm Cancer. 2:47–61. 2011. View Article : Google Scholar : PubMed/NCBI

Rizzo S, Attard G and Hudson DL: Prostate epithelial stem cells. Cell Prolif. 38:363–374. 2005. View Article : Google Scholar : PubMed/NCBI

Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ and Collins AT: CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci. 117:3539–3545. 2004. View Article : Google Scholar : PubMed/NCBI

Collins AT, Berry PA, Hyde C, Stower MJ and Maitland NJ: Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65:10946–10951. 2005. View Article : Google Scholar : PubMed/NCBI

Maitland NJ and Collins A: A tumour stem cell hypothesis for the origins of prostate cancer. BJU Int. 96:1219–1223. 2005. View Article : Google Scholar : PubMed/NCBI

Nicolis SK: Cancer stem cells and ‘stemness’ genes in neuro-oncology. Neurobiol Dis. 25:217–229. 2007. View Article : Google Scholar : PubMed/NCBI

Wang S, Huang S, Zhao X, Zhang Q, Wu M, Sun F, Han G and Wu D: Enrichment of prostate cancer stem cells from primary prostate cancer cultures of biopsy samples. Int J Clin Exp Pathol. 7:184–193. 2013.PubMed/NCBI

Tárnok A, Ulrich H and Bocsi J: Phenotypes of stem cells from diverse origin. Cytometry A. 77:6–10. 2010. View Article : Google Scholar : PubMed/NCBI

Ojo D, Lin X, Wong N, Gu Y and Tang D: Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer. Cancers (Basel). 7:2290–2308. 2015. View Article : Google Scholar : PubMed/NCBI

Guo Z, Huang H, Zeng L, Du T, Xu K, Lin T, Jiang C, Dong W, Cao Y, Chen J, et al: Lentivirus-mediated RNAi knockdown of prostate-specific membrane antigen suppresses growth, reduces migration ability and the invasiveness of prostate cancer cells. Med Oncol. 28:878–887. 2011. View Article : Google Scholar : PubMed/NCBI

Nadiminty N, Lou W, Lee SO, Lin X, Trump DL and Gao AC: Stat3 activation of NF-(kappa)B p100 processing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA. 103:pp. 7264–7269. 2006; View Article : Google Scholar : PubMed/NCBI

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 367:1187–1197. 2012. View Article : Google Scholar : PubMed/NCBI

Cindolo L, Natoli C, De Nunzio C, De Tursi M, Valeriani M, Giacinti S, Micali S, Rizzo M, Bianchi G, Martorana E, et al: Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer in chemotherapy-naive patients: An Italian analysis of patients' satisfaction. Clin Genitourin Cancer. 15:520–525. 2017. View Article : Google Scholar : PubMed/NCBI

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 363:411–422. 2010. View Article : Google Scholar : PubMed/NCBI

Inamoto T and Azuma H: Overview of the ongoing clinical trials for new treatments for castrate-resistant prostate cancer (CRPC). Nihon Rinsho. 74 Suppl 3:S653–S659. 2016.(In Japanese).

Penning TM: Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC). J Steroid Biochem Mol Biol. 153:105–113. 2015. View Article : Google Scholar : PubMed/NCBI