全部 标题 作者
关键词 摘要


Looking beyond Androgen Receptor Signaling in the Treatment of Advanced Prostate Cancer

DOI: 10.1155/2014/748352

Full-Text   Cite this paper   Add to My Lib

Abstract:

This review will provide a description of recent efforts in our laboratory contributing to a general goal of identifying critical determinants of prostate cancer growth in both androgen-dependent and -independent contexts. Important outcomes to date have indicated that the sustained activation of AR transcriptional activity in castration-resistant prostate cancer (CRPC) cells results in a gene expression profile separate from the androgen-responsive profile of androgen-dependent prostate cancer (ADPC) cells. Contributing to this reprogramming is enhanced FoxA1 recruitment of AR to G2/M phase target gene loci and the enhanced chromatin looping of CRPC-specific gene regulatory elements facilitated by PI3K/Akt-phosphorylated MED1. We have also observed a role for FoxA1 beyond AR signaling in driving G1/S phase cell cycle progression that relies on interactions with novel collaborators MYBL2 and CREB1. Finally, we describe an in-depth mechanism of GATA2-mediated androgen-responsive gene expression in both ADPC and CRPC cells. Altogether these efforts provide evidence to support the development of novel prostate cancer therapeutics that address downstream targets of AR activity as well as AR-independent drivers of disease-relevant transcription programs. 1. Introduction The androgen receptor (AR), a member of the steroid receptor superfamily [1], is a classic example of a ligand-inducible transcription factor whose activity is tightly linked to numerous physiological processes and disease states. Within the various mammalian tissues expressing AR, its essential role in organ development and function has been demonstrated, which ranges from contributions to spermatogenesis, sexual behavior, and skeletal maintenance [2]. Mechanistically, induction of AR activity relies upon binding to male hormones, androgens (e.g., testosterone or the more potent 5α-dihydrotestosterone [DHT]), resulting in release of AR from stabilizing interactions with cytoplasmic heat shock proteins (HSPs) [3]. Homodimerization, activation by posttranslational modification, and nuclear translocation of ligand-bound AR is then essential for its established role in determining tissue-, cell type-, and disease stage-specific gene expression patterns [3]. Within the nucleus, AR binds genomic regions enriched with its cognate DNA-binding motif, or androgen response element (ARE), consisting classically of the 15-base pair sequence 5′-AGAACAnnnTGTTCT-3′ and providing a degree of specificity to global AR distribution within regulatory elements of androgen responsive genes [4]. These regulatory

References

[1]  P. J. Fuller, “The steroid receptor superfamily: mechanisms of diversity,” The FASEB Journal, vol. 5, no. 15, pp. 3092–3099, 1991.
[2]  K. de Gendt and G. Verhoeven, “Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice,” Molecular and Cellular Endocrinology, vol. 352, no. 1-2, pp. 13–25, 2012.
[3]  M. M. Centenera, J. M. Harris, W. D. Tilley, and L. M. Butler, “The contribution of different androgen receptor domains to receptor dimerization and signaling,” Molecular Endocrinology, vol. 22, no. 11, pp. 2373–2382, 2008.
[4]  F. Claessens, S. Denayer, N. van Tilborgh, S. Kerkhofs, C. Helsen, and A. Haelens, “Diverse roles of androgen receptor (AR) domains in AR-mediated signaling,” Nuclear Receptor Signaling, vol. 6, article e008, 2008.
[5]  C. A. Heinlein and C. Chang, “Androgen receptor in prostate cancer,” Endocrine Reviews, vol. 25, no. 2, pp. 276–308, 2004.
[6]  C. Huggins and P. J. Clark, “Quantitative studies of prostatic secretion: II. The effect of castration and of estrogen injection on the normal and on the hyperplastic prostate glands of dogs,” The Journal of Experimental Medicine, vol. 72, no. 6, pp. 747–762, 1940.
[7]  C. Huggins and R. A. Stevens, “The effect of castration on benign hypertrophy of the prostate in man,” The Journal of Urology, vol. 43, article 105, 1940.
[8]  C. Huggins and C. V. Hodges, “Studies on prostate cancer: I. The effects of castration of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate,” Cancer Research, vol. 1, article 203, 1941.
[9]  S. R. Denmeade and J. T. Isaacs, “A history of prostate cancer treatment,” Nature Reviews Cancer, vol. 2, no. 5, pp. 389–396, 2002.
[10]  G. Tolis, D. Ackman, and A. Stellos, “Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 5, pp. 1658–1662, 1982.
[11]  E. J. Sanford, J. R. Drago, and T. J. Rohner Jr., “Aminoglutethimide medical adrenalectomy for advanced prostatic carcinoma,” The Journal of Urology, vol. 115, no. 2, pp. 170–174, 1976.
[12]  K. M. Anderson and S. Liao, “Selective retention of dihydrotestosterone by prostatic nuclei,” Nature, vol. 219, no. 5151, pp. 277–279, 1968.
[13]  N. Bruchovsky and J. D. Wilson, “The intranuclear binding of testosterone and 5-alpha-androstan-17-beta-ol-3-one by rat prostate,” The Journal of Biological Chemistry, vol. 243, no. 22, pp. 5953–5960, 1968.
[14]  W. I. Mainwaring, “A soluble androgen receptor in the cytoplasm of rat prostate,” Journal of Endocrinology, vol. 45, no. 4, pp. 531–541, 1969.
[15]  S. Liao, D. K. Howell, and T. M. Chang, “Action of a nonsteroidal antiandrogen, flutamide, on the receptor binding and nuclear retention of 5α- dihydrotestosterone in rat ventral prostate,” Endocrinology, vol. 94, no. 4, pp. 1205–1209, 1974.
[16]  K. E. Knudsen and H. I. Scher, “Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer,” Clinical Cancer Research, vol. 15, no. 15, pp. 4792–4798, 2009.
[17]  Y. Chen, C. L. Sawyers, and H. I. Scher, “Targeting the androgen receptor pathway in prostate cancer,” Current Opinion in Pharmacology, vol. 8, no. 4, pp. 440–448, 2008.
[18]  D. A. Loblaw, K. S. Virgo, R. Nam et al., “Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology Practice Guideline,” Journal of Clinical Oncology, vol. 25, no. 12, pp. 1596–1605, 2007.
[19]  J. D. Debes and D. J. Tindall, “Mechanisms of androgen-refractory prostate cancer,” The New England Journal of Medicine, vol. 351, no. 15, pp. 1488–1490, 2004.
[20]  B. J. Feldman and D. Feldman, “The development of androgen-independent prostate cancer,” Nature Reviews Cancer, vol. 1, no. 1, pp. 34–45, 2001.
[21]  K. E. Knudsen and T. M. Penning, “Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer,” Trends in Endocrinology & Metabolism, vol. 21, no. 5, pp. 315–324, 2010.
[22]  C. Tran, S. Ouk, N. J. Clegg et al., “Development of a second-generation antiandrogen for treatment of advanced prostate cancer,” Science, vol. 324, no. 5928, pp. 787–790, 2009.
[23]  H. I. Scher, K. Fizazi, F. Saad et al., “Increased survival with enzalutamide in prostate cancer after chemotherapy,” The New England Journal of Medicine, vol. 367, no. 13, pp. 1187–1197, 2012.
[24]  G. Attard, A. H. Reid, T. A. Yap et al., “Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven,” Journal of Clinical Oncology, vol. 26, no. 28, pp. 4563–4571, 2008.
[25]  G. Attard, A. H. Reid, R. A'Hern et al., “Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer,” Journal of Clinical Oncology, vol. 27, no. 23, pp. 3742–3748, 2009.
[26]  J. S. de Bono, C. J. Logothetis, A. Molina et al., “Abiraterone and increased survival in metastatic prostate cancer,” The New England Journal of Medicine, vol. 364, no. 21, pp. 1995–2005, 2011.
[27]  V. Tzelepi, J. Zhang, J.-F. Lu et al., “Modeling a lethal prostate cancer variant with small-cell carcinoma features,” Clinical Cancer Research, vol. 18, no. 3, pp. 666–677, 2012.
[28]  G. Attard, C. S. Cooper, and J. S. de Bono, “Steroid hormone receptors in prostate cancer: a hard habit to break?” Cancer Cell, vol. 16, no. 6, pp. 458–462, 2009.
[29]  M. J. Linja, K. J. Savinainen, O. R. Saramaki, T. L. J. Tammela, R. L. Vessella, and T. Visakorpi, “Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer,” Cancer Research, vol. 61, no. 9, pp. 3550–3555, 2001.
[30]  A. Latil, I. Bieche, D. Vidaud et al., “Evaluation of androgen, estrogen (ERα and ERβ), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays,” Cancer Research, vol. 61, no. 5, pp. 1919–1926, 2001.
[31]  T. Hara, J.-I. Miyazaki, H. Araki et al., “Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome,” Cancer Research, vol. 63, no. 1, pp. 149–153, 2003.
[32]  M. Korpal, J. M. Korn, X. Gao et al., “An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide),” Cancer Discovery, vol. 3, no. 9, pp. 1030–1043, 2013.
[33]  J. D. Joseph, N. Lu, J. Qian et al., “A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509,” Cancer Discovery, vol. 3, no. 9, pp. 1020–1029, 2013.
[34]  S. M. Dehm, L. J. Schmidt, H. V. Heemers, R. L. Vessella, and D. J. Tindall, “Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance,” Cancer Research, vol. 68, no. 13, pp. 5469–5477, 2008.
[35]  R. Hu, T. A. Dunn, S. Wei et al., “Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer,” Cancer Research, vol. 69, no. 1, pp. 16–22, 2009.
[36]  Z. Guo, X. Yang, F. Sun et al., “A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth,” Cancer Research, vol. 69, no. 6, pp. 2305–2313, 2009.
[37]  J. A. Locke, E. S. Guns, A. A. Lubik et al., “Androgen Levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer,” Cancer Research, vol. 68, no. 15, pp. 6407–6415, 2008.
[38]  R. B. Montgomery, E. A. Mostaghel, R. Vessella et al., “Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth,” Cancer Research, vol. 68, no. 11, pp. 4447–4454, 2008.
[39]  M. Stanbrough, G. J. Bubley, K. Ross et al., “Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer,” Cancer Research, vol. 66, no. 5, pp. 2815–2825, 2006.
[40]  L. A. Ponguta, C. W. Gregory, F. S. French, and E. M. Wilson, “Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer,” The Journal of Biological Chemistry, vol. 283, no. 30, pp. 20989–21001, 2008.
[41]  M.-L. Zhu and N. Kyprianou, “Androgen receptor and growth factor signaling cross-talk in prostate cancer cells,” Endocrine-Related Cancer, vol. 15, no. 4, pp. 841–849, 2008.
[42]  R. Chmelar, G. Buchanan, E. F. Need, W. Tilley, and N. M. Greenberg, “Androgen receptor coregulators and their involvement in the development and progression of prostate cancer,” International Journal of Cancer, vol. 120, no. 4, pp. 719–733, 2007.
[43]  C. W. Gregory, B. He, R. T. Johnson et al., “A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy,” Cancer Research, vol. 61, no. 11, pp. 4315–4319, 2001.
[44]  I. U. Agoulnik, A. Vaid, W. E. Bingman III et al., “Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression,” Cancer Research, vol. 65, no. 17, pp. 7959–7967, 2005.
[45]  M. P. Steinkamp, O. A. O'Mahony, M. Brogley et al., “Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy,” Cancer Research, vol. 69, no. 10, pp. 4434–4442, 2009.
[46]  American Cancer Society, Cancer Facts and Figures 2012, Atlanta, Ga, USA, American Cancer Society edition, 2012.
[47]  S. P. Balk and K. E. Knudsen, “AR, the cell cycle, and prostate cancer,” Nuclear Receptor Signaling, vol. 6, article e001, 2008.
[48]  Q. Wang, W. Li, Y. Zhang et al., “Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer,” Cell, vol. 138, no. 2, pp. 245–256, 2009.
[49]  C. E. Massie, A. Lynch, A. Ramos-Montoya et al., “The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis,” The EMBO Journal, vol. 30, no. 13, pp. 2719–2733, 2011.
[50]  Y. Ye and M. Rape, “Building ubiquitin chains: E2 enzymes at work,” Nature Reviews Molecular Cell Biology, vol. 10, no. 11, pp. 755–764, 2009.
[51]  J. H. van Ree, K. B. Jeganathan, L. Malureanu, and J. M. van Deursen, “Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation,” The Journal of Cell Biology, vol. 188, no. 1, pp. 83–100, 2010.
[52]  R. Hu, C. Lu, E. A. Mostaghel et al., “Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer,” Cancer Research, vol. 72, no. 14, pp. 3457–3462, 2012.
[53]  K. Xu, Z. J. Wu, A. C. Groner et al., “EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent,” Science, vol. 338, no. 6113, pp. 1465–1469, 2012.
[54]  L. K. Povlsen, P. Beli, S. A. Wagner et al., “Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass,” Nature Cell Biology, vol. 14, no. 10, pp. 1089–1098, 2012.
[55]  N. L. Sharma, C. E. Massie, A. Ramos-Montoya et al., “The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man,” Cancer Cell, vol. 23, no. 1, pp. 35–47, 2013.
[56]  H. Wang, C. Zhang, A. Rorick et al., “CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability,” Cancer Research, vol. 71, no. 14, pp. 4866–4876, 2011.
[57]  S. Chen, Y. Chen, C. Hu, H. Jing, Y. Cao, and X. Liu, “Association of clinicopathological features with UbcH10 expression in colorectal cancer,” Journal of Cancer Research and Clinical Oncology, vol. 136, no. 3, pp. 419–426, 2010.
[58]  D. Loussouarn, L. Campion, F. Leclair et al., “Validation of UBE2C protein as a prognostic marker in node-positive breast cancer,” British Journal of Cancer, vol. 101, no. 1, pp. 166–173, 2009.
[59]  I. W. Cunha, K. C. Carvalho, W. K. Martins et al., “Identification of genes associated with local aggressiveness and metastatic behavior in soft tissue tumors,” Translational Oncology, vol. 3, no. 1, pp. 23–32, 2010.
[60]  Q. Wang, C. G. Bailey, C. Ng et al., “Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression,” Cancer Research, vol. 71, no. 24, pp. 7525–7536, 2011.
[61]  S. R. Kimball, L. M. Shantz, R. L. Horetsky, and L. S. Jefferson, “Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6,” The Journal of Biological Chemistry, vol. 274, no. 17, pp. 11647–11652, 1999.
[62]  Q. Wang, J. Tiffen, C. G. Bailey et al., “Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development,” Journal of the National Cancer Institute, vol. 105, no. 19, pp. 1463–1473, 2013.
[63]  K. S. Zaret and J. S. Carroll, “Pioneer transcription factors: establishing competence for gene expression,” Genes & Development, vol. 25, no. 21, pp. 2227–2241, 2011.
[64]  J. R. Friedman and K. H. Kaestner, “The Foxa family of transcription factors in development and metabolism,” Cellular and Molecular Life Sciences, vol. 63, no. 19-20, pp. 2317–2328, 2006.
[65]  L. A. Cirillo, C. E. McPherson, P. Bossard et al., “Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome,” The EMBO Journal, vol. 17, no. 1, pp. 244–254, 1998.
[66]  L. A. Cirillo, F. R. Lin, I. Cuesta, D. Friedman, M. Jarnik, and K. S. Zaret, “Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4,” Molecular Cell, vol. 9, no. 2, pp. 279–289, 2002.
[67]  M. Lupien, J. Eeckhoute, C. A. Meyer et al., “FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription,” Cell, vol. 132, no. 6, pp. 958–970, 2008.
[68]  C. Zhang, L. Wang, D. Wu et al., “Definition of a FoxA1 cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer,” Cancer Research, vol. 71, no. 21, pp. 6738–6748, 2011.
[69]  E. LaTulippe, J. Satagopan, A. Smith et al., “Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease,” Cancer Research, vol. 62, no. 15, pp. 4499–4506, 2002.
[70]  Y. P. Yu, D. Landsittel, L. Jing et al., “Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy,” Journal of Clinical Oncology, vol. 22, no. 14, pp. 2790–2799, 2004.
[71]  S. Varambally, J. Yu, B. Laxman et al., “Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression,” Cancer Cell, vol. 8, no. 5, pp. 393–406, 2005.
[72]  A. P. Kumar, S. Bhaskaran, M. Ganapathy et al., “Akt/cAMP-responsive element binding protein/cyclin D1 network: a novel target for prostate cancer inhibition in transgenic adenocarcinoma of mouse prostate model mediated by Nexrutine, a Phellodendron amurense bark extract,” Clinical Cancer Research, vol. 13, no. 9, pp. 2784–2794, 2007.
[73]  D. Wu, H. E. Zhau, W.-C. Huang et al., “cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis,” Oncogene, vol. 26, no. 35, pp. 5070–5077, 2007.
[74]  E. D. Martinez and M. Danielsen, “Loss of androgen receptor transcriptional activity at the G1/S transition,” The Journal of Biological Chemistry, vol. 277, no. 33, pp. 29719–29729, 2002.
[75]  I. V. Litvinov, D. J. Vander Griend, L. Antony et al., “Androgen receptor as a licensing factor for DNA replication in androgen-sensitive prostate cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 41, pp. 15085–15090, 2006.
[76]  D. Wu, B. Sunkel, Z. Chen et al., “Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer,” Nucleic Acids Research, vol. 42, no. 6, pp. 3607–3622, 2014.
[77]  Q. Jin, L.-R. Yu, L. Wang et al., “Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation,” The EMBO Journal, vol. 30, no. 2, pp. 249–262, 2011.
[78]  E. Calo and J. Wysocka, “Modification of enhancer chromatin: what, how, and why?” Molecular Cell, vol. 49, no. 5, pp. 825–837, 2013.
[79]  S. Shah, S. Prasad, and K. E. Knudsen, “Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression,” Cancer Research, vol. 72, no. 5, pp. 1248–1259, 2012.
[80]  F. Hayakawa, M. Towatari, Y. Ozawa, A. Tomita, M. L. Privalsky, and H. Saito, “Functional regulation of GATA-2 by acetylation,” Journal of Leukocyte Biology, vol. 75, no. 3, pp. 529–540, 2004.
[81]  C. R. Vakoc, D. L. Letting, N. Gheldof et al., “Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1,” Molecular Cell, vol. 17, no. 3, pp. 453–462, 2005.
[82]  B. Sahu, M. Laakso, K. Ovaska et al., “Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer,” The EMBO Journal, vol. 30, no. 19, pp. 3962–3976, 2011.
[83]  D. Wang, I. Garcia-Bassets, C. Benner et al., “Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA,” Nature, vol. 474, no. 7351, pp. 390–394, 2011.
[84]  V. Theodorou, R. Stark, S. Menon, and J. S. Carroll, “GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility,” Genome Research, vol. 23, no. 1, pp. 12–22, 2013.
[85]  M. Bohm, W. J. Locke, R. L. Sutherland, J. G. Kench, and S. M. Henshall, “A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes,” Oncogene, vol. 28, no. 43, pp. 3847–3856, 2009.
[86]  R. B. Shah, R. Mehra, A. M. Chinnaiyan et al., “Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program,” Cancer Research, vol. 64, no. 24, pp. 9209–9216, 2004.
[87]  Z. G. Li, P. Mathew, J. Yang et al., “Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms,” The Journal of Clinical Investigation, vol. 118, no. 8, pp. 2697–2710, 2008.
[88]  Z. Chen, C. Zhang, D. Wu et al., “Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth,” The EMBO Journal, vol. 30, no. 12, pp. 2405–2419, 2011.
[89]  S. Malik and R. G. Roeder, “The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation,” Nature Reviews Genetics, vol. 11, no. 11, pp. 761–772, 2010.
[90]  L. Li, M. M. Ittmann, G. Ayala et al., “The emerging role of the PI3-K-Akt pathway in prostate cancer progression,” Prostate Cancer and Prostatic Diseases, vol. 8, no. 2, pp. 108–118, 2005.
[91]  P. K. Majumder and W. R. Sellers, “Akt-regulated pathways in prostate cancer,” Oncogene, vol. 24, no. 50, pp. 7465–7474, 2005.
[92]  F. Jin, S. Irshad, W. Yu et al., “ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity,” Molecular Cancer Research, vol. 11, no. 7, pp. 736–747, 2013.

Full-Text

comments powered by Disqus