In recent years, multiple genes or their protein products have been linked to initiation and progression of prostate cancer. Such genes include TMPRSS2, ERG, PTEN, and MDM2. This chapter discusses the pathological roles as well as the potential diagnostic and therapeutic applications of these genes that are highly expressed in prostate cancer when compared to other cancer types. The presence of these genes and related defects are linked to growth, progression, metastasis, invasiveness and resistance in prostate cancers. While knowledge related to TMPRSS2, ERG, and PTEN have been accumulating in the last two decades, the prometastatic role of MDM2 has been emerging in the last few years and revealing important functions related to prostate cancer progression.
- prostate cancer
Prostate cancer (PCa) is a long latency tumor that occurs in males that are typically aged 50 years and older. Globally, more than 1.1 million cases of prostate cancer were recorded in 2012, accounting for around 8% of all new cancer cases and 15% in men . In 2015, an estimated 220,800 men will be diagnosed with PCa in the United States and an estimated 27,540 men will die due to the disease making this malignancy the second leading cause of cancer-related death in men . In addition, African-American (AA) men have the highest incidence and mortality from PCa when compared to other races . The pathophysiology of prostate cancer is not fully elucidated, but it is well established that this dreadful disease is primarily initiated by cellular proliferation within pre-existing ducts and glands, which is referred to as Prostatic intraepithelial neoplasia (PIN). The PIN eventually progresses to invasive prostate cancer . Clinical manifestations of the disease are variable and based on the transport by blood or the lymphatic system to metastatic sites and the effects of localized tumor growth. Localized prostate cancer is typically curable with targeted local therapy such as radical prostatectomy or radiation therapy. In metastatic prostate cancer, one of the successful strategies of treatment is surgical or chemical castration leading to androgen deprivation therapy (ADT) . Unfortunately, approximately 33% of patients develop resistance to these treatments with the eventual increases in the number of androgens, prostate specific antigen (PSA), and circulating tumor cells (CTCs), leading to the more progressive and metastatic castration resistant prostate cancer (CRPC) . The poor prognosis associated with metastatic prostate cancers is attributable in part to the highly heterogeneous nature of the cancer cells, which provides a significant hurdle for treatment of the disease . Multiple genomic alterations underlie the clinical heterogeneity of prostate cancer and such aberrations include, point mutations, microsatellite variations, and chromosomal alterations such as translocations, insertions, duplications, fusions, and deletions [6, 7]. Therefore, there is a heightened interest in understanding the role of these genetic changes in prostate cancer development and progression.
2. Key genes in prostate cancer progression
In the past decade, several genes associated with prostate cancer have been identified. Four such genes: the ETS-related gene (ERG), The Transmembrane Protease Serine 2 (TMPRSS2), Mouse double minute 2 homolog (MDM2), and Phosphatase and tensin homolog (PTEN) have gained recognition for their high specificity of expression in prostatic carcinomas.
2.1. Prostate cancer and PTEN
PTEN is a protein coding gene that encodes for phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin-like domain in addition to a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. PTEN is one of the most commonly mutated tumor suppressor genes in human prostate cancer. Interestingly, many aspects of PTEN expression and function, including transcriptional and post-transcriptional regulation, post-translational modifications, and protein-protein interactions have been shown to be altered in human prostate cancer. PTEN is a non-redundant phosphatase that directly interferes with the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and thereby controls several processes that are important in the homeostasis of cell survival and a multitude of cellular functions, which includes growth, proliferation, metabolism, migration, and cellular architecture . PTEN removes the phosphate from the D3 position of phosphatidylinositol-3,4,5-triphosphate (PIP3), a product of PI3K, thus, can lead to inhibition of downstream AKT activation in normal conditions. However, when PTEN is mutated there is sustained activation of AKT that can lead to cell proliferation, angiogenesis and other related events. AKT exists in three isoforms, namely AKT1, AKT2, and AKT3, which are typically activated by the phosphorylation at two specific sites: Thr308 by PDK1  and Ser473 by the mammalian target of rapamycin complex 2 (mTORC2) . Activated AKT can drive cell survival, proliferation, growth, angiogenesis, and metabolism by phosphorylating downstream signaling proteins, which include inhibitory phosphorylation of GSK3, FOXO, BAD, p21, p27, and PGC I and activating phosphorylation of mTORC I mammalian target of rapamycin complex I (mTORC I), IKK-β, MDM2, ENTPD5, SREBP1C, AS160, and SKP2, which eventually leads to cell cycle progression and proliferation [10, 11]. Inhibition of GSK3β has been shown to specifically prevent the degradation of cyclin D1 and β-catenin, which can further support G1 to S phase transition in different types of cancers including prostate cancers [11, 12]. Activation of AKT also helps to evade apoptosis directly by phosphorylation of the pro-apoptotic protein BAD . Hence, re-expression of wild-type
2.1.1. PTEN loss combined with alterations in inflammatory pathway regulators
Various lines of evidence suggest that chronic inflammation is a closely associated event in the tumorigenic mechanisms of prostate cancer [29, 30] and to the several mutations that are causing this disease. A cytokine that is most commonly associated with tumor growth, proliferation, and angiogenesis in many cancers and also the most frequently found inflammatory mediator in prostate cancer is IL-6 . When expressed at high levels, in addition to imposing the inflammatory functions, a strong correlation between the circulating levels of IL-6 and advancement in the stages of prostate cancer, therapeutic resistance, and as a result an overall poor prognosis has been well established until now . Although one of the most important consequences of IL-6 expression is the stimulation of the JAK/STAT3 pathway , phosphorylation of STAT3 at Scr727 and activation of its function by the PI3K-AKT pathway cannot be ruled out completely because of the impact PTEN mutations can produce on this pathway . Such activation of STAT3 can also lead to metastatic behavior of prostate cancer cells in both
2.2. MDM2 and prostate cancer
Alterations in the
2.2.1. MDM2 and cytokine expression
In addition to being the trigger for developing cancers, MDM2 expression seems to be responsible for several events that promote cancer aggressiveness . Increased expression of VEGF in cancer cells, which are positive for MDM2, is a well-established phenomenon that occurs through elevation of HIF-1alpha even during the absence of hypoxia in the tumor microenvironment . In addition, many reports in the literature confirm that MDM2 overexpression could lead to activation of STAT3 and NF-κB pathways and cause elevation of cytokines that in-turn can stimulate cancer progression. One of the unique biological functions of MDM2 is its ability to induce sterile tissue inflammation, which is a major element of non-infectious tissue injury that occurs following exposure to toxins or reperfusion following ischemia. For example, an acute post-ischemic kidney injury that started as a sterile inflammatory response was reversed using the MDM2 blockade with nutlin-3 . This effect was found to be totally independent of p53 that was observed in a p53-deficient mice. Also, MDM2 blockade effectively suppressed the post-ischemic induction of pro-inflammatory cytokines and chemokines as well as the infiltration of leukocytes to the site of injury. Following these observations, the mechanism underlying MDM2-mediated inflammation was identified under
2.3. TMPRSS2 and ERG fusions in prostate cancer
TMPRSS2 is an androgen regulated prostate-specific protein that is encoded in humans by the TMPRSS2 gene . It is a 492 amino acid type II transmembrane serine protease (70 KDa) that is expressed at the cell surface in order to regulate cell-cell and cell-matrix interactions . The serine protease gene family, play crucial roles in different physiological and pathological processes such as digestion, blood coagulation, remodeling of tissues, invasion of tumor cells, inflammatory responses, and apoptosis. The TMPRSS2 protein contains a Serine protease domain (aa 255-492) with three catalytic residues of histidine, aspartate, and serine, respectively, a Scavenger receptor cysteine-rich domain (SRDR, aa 149-242), an LDL receptor class A (LDLRA, aa 113-148) domain and a predicted transmembrane domain (aa 84-106) .
ERG is a member of the erythroblastosis virus E26 (ETS) oncogene family. There are over 20 ETS transcription factor family members, but ERG is the ETS transcription factor primarily involved in prostate cancer gene fusions . The ERG protein interacts with ETS members as well as other transcription factors through its protein-protein interacting domain to regulate transcriptional activity of several downstream target genes that are crucial for DNA damage, cell invasion and proliferation, epithelial to mesenchymal transformation (EMT) as well as cellular differentiation and epigenetic control [66–68].
TMPRSS2 is expressed in normal and neoplastic prostate tissue and is strongly induced by androgens in androgen-sensitive prostate cell lines . A major milestone in PCa research was the identification of recurrent fusions between TMPRSS2 and ERG . TMPRSS2-ERG is fused in PCa through deletion of genomic DNA via a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2 or through translocation or both [69–71]. These rearrangements (Figure 1) result in the formation of a TMPRSS2-ERG fusion transcript and the overexpression of ERG . The TMPRSS2 and ERG genes are both located on the same chromosome (21q) and the distance between the TMPRSS2 and ERG oncogene is relatively short at 3 mega bases (MB) (Figure 3). This short distance has been suggested to account for the higher frequency of TMPRSS2: ERG fusions in prostate cancer [69, 73].
TMPRSS2-ERG fusion occurs early in prostate carcinogenesis at the transition between benign and prostatic intraepithelial neoplasia (PIN). Approximately 50% of PCas from prostate-specific antigen (PSA) screened surgical cohorts are TMPRSS2-ERG fusion-positive, and >90% of PCas over-expressing ERG harbor TMPRSS2-ERG fusions . Over eight isoforms of the TMPRSS2-ERG fusion transcript have been identified with varying levels of expression in different PCa samples . The most frequently found TMPRSS2-ERG fusion in PCa is the deletion between the 5 UTR end of TMPRSS2 exon 1 and 5 end of ERG exon 4 .
2.3.1. Consequences of TMPRSS2-ERG fusion in prostate cancer
TMPRSS2 is an androgen-responsive gene and AR regulated expression of the TMPRSS2-ERG fusion gene plays an early role in prostate cancer development and progression as its presence is required for prostate cancer initiation in ETS positive tumors . The fusion results in the modulation of transcriptional patterns and cellular pathways causing the development of prostatic intraepithelial neoplasia (PIN) . In particular, gene expression profiling has linked a deregulation of WNT and TGF-β/BMP signaling in fusion-positive prostate tumors . It has also been shown in transgenic mice that overexpression of ERG as a result of TMPRSS2: ERG fusion leads to the formation of murine PIN (mPIN) by 5–6 months of age [74, 79]. Several studies have also confirmed that the overexpression of ERG leads to prostate cell migration and invasion that correlates with increased tumor metastasis and negative patient outcome [79, 80]. The most prominent role of ERG that has been consistently shown is its ability to increase cell migration and invasion via abrogating prostate epithelial differentiation and inducing epithelial to mesenchymal transition and motility-associated genes such as MMPs .
PCa specimens containing the TMPRSS2-ERG rearrangement are also significantly enriched for the loss of tumor suppressor gene phosphatase and tensin homologue PTEN , and it is already well established that aberrant PTEN activity is associated with poor prognosis in PCa . Further studies have confirmed that TMPRSS2-ERG rearrangement cooperates with PTEN loss to promote prostate cancer progression from high-grade prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinoma [77, 83].
2.3.2. TMPRSS2-ERG fusions and ethnicity
There are several studies evaluating the relationship between ethnicity and TMPRSS2-ERG expression in PCa. TMPRSS2-ERG gene fusion correlated with ethnicity in a multivariate analysis involving Caucasians , African-Americans, and Japanese men with PCa . TMPRSS2-ERG gene fusion was present in 50% (21/42) of Caucasians, 31.3% (20/64) of African-Americans, and 15.9% (7/44) of Japanese patients. A subsequent study found that TMPRSS2-ERG gene fusions were identified in 48/112 tumors (42.9%) from a group of Caucasian men, while 28/105 tumors (26.7%; p = 0.015) from African-American men were positive for the gene fusion . Interestingly, Mosquera and colleagues recognized that the TMPRSS2-ERG fusion through deletion, which has been associated with worse prognosis, is more common in PCa of African-American patients .
2.3.3. Prognostic value of the TMPRSS2-ERG fusion gene
The prognostic potential of TMPRSS2-ERG gene fusion is promising as it can be detected in urine, blood, and tissue using quantitative polymerase chain reaction [85, 86], Fluorescence in situ hybridization (FISH) , DNA sequencing, and Genechip . This has significant applications toward understanding its role in PCa pathogenesis and developing novel diagnostics and targeted therapeutics. TMPRSS2 and TMPRSS2-ERG expression is decreased in response to ADT in primary PCa . Interestingly, the ERG levels in TMPRSS2-ERG fusion-positive castration resistant prostate cancer CRPC are comparable with the levels in fusion gene-positive primary PC, and this confirms that TMPRSS2-ERG expression is reactivated by AR in CRPC . These findings prove that restored AR receptor signaling contributes to the progression to CRPC in part through the TMPRSS2-ERG axis and highlights a therapeutic platform that can be explored in the management of CRPC. More recently, the TMPRSS2-ERG fusion has been linked to taxane resistance in preclinical models of castration-resistant prostate cancer, and TMPRSS2-ERG expression detection in the peripheral blood of metastatic castration-resistant prostate cancer patients correlates with docetaxel resistance . Therefore, its presence predicts resistance to docetaxel, and it may be useful to select treatment and to avoid possible toxicities in refractory patients.
The author Appu Rathinavelu, Ph.D., would like to thank the Fulbright Scholar Program of the United States Department of State Bureau of Educational and Cultural Affairs and the USIEF (United States International Educational Foundation) for the Nehru—Fulbright Scholar Award during the completion of this book chapter. The author would also like to Thank Nova Southeastern University and the Royal Dames of Ft. Lauderdale Inc, Florida, USA for their support.
Ferlay J, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin D, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in Globocan 2012. Int J Cancer. 2015; 136(5): E359–E386. doi:10.1002/ijc.29210
Siegel R, Miller K, Jemal A. Cancer Statistics 2015. CA Cancer J Clin. 2015; 65: 5–29. doi:10.3322/caac.21254
Bostwick DG. High-grade prostatic intraepithelial neoplasia: The most likely precursor of prostate cancer. Cancer. 1995; 75: 1823–1836. doi:10.1002/1097-0142(19950401)75: 7+<1823::aid-cncr2820751612>3.0.co;2-7
Massard C, Fizazi K. Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res. 2011; 17(12): 3876–3883. doi:10.1158/1078-0432.ccr-10-2815
Yap T, Swanton C, De Bono1 J. Personalization of prostate cancer prevention and therapy are clinically qualified biomarkers in the horizon? EPMA J. 2012; 3(1): 3. doi:10.1007/s13167-011-0138-2
Boyd L, Mao X, Lu Y. The complexity of prostate cancer: Genomic alterations and heterogeneity. Nat Rev Urol. 2012; 9: 652–664. doi:10.1038/nrurol.2012.185
Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: New prospects for old challenges. Genes Dev. 2010; 24(18): 1967–2000. doi:10.1101/gad.1965810
Tindall D, editor. Prostate Cancer: Biochemistry, Molecular Biology and Genetics. 1st ed. Springer-Verlag: New York; 2013. 518 p. doi:10.1007/978-1-4614-6828-8
Manning BD, Cantley LC. AKT/PKB signaling: Navigating downstream. Cell. 2007; 129(7): 1261–1274. doi:10.1016/j.cell.2007.06.009
Zoncu R, Efeyan A, Sabatini D. MTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12(1): 21–35. doi:10.1038/nrm3025
De la Taille A, Rubin M, Chen M, Vacherot F, De Medina S, Burchardt M, Buttyan R, Chopin D. Beta-catenin-related anomalies in apoptosis-resistant and hormone refractory prostate cancer cells. Clin Cancer Res. 2003; 9: 1801–1807.
Lee H, Kwak H, Hur J, Kim I, Yang J, Park M, Yu J, Jeong S. Beta-catenin regulates multiple steps of RNA metabolism as revealed by the RNA aptamer in colon cancer cells. Cancer Res. 2007; 6 7: 9315–9321. doi:10.1158/0008-5472.CAN-07-1128
Grunwald V, DeGraffenried L, Russel D, Friedrichs W, Ray R, Hidalgo M. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res. 2002; 62: 6141–6145.
Wu X, Senechal K, Neshat M, Whang Y, Sawyers C. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1998; 95: 15587–15591. doi:10.1073/pnas.95.26.15587
Guertin D, Sabatini D. Defining the role of mTOR in cancer. Cancer Cell. 2007; 12: 9–22. doi:10.1016/j.ccr.2007.05.008
Ma X, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009; 10: 307–318. doi:10.1038/nrm2672
Denu J, Stuckey J, Saper M, Dixon J. Form and function in protein dephosphorylation. Cell. 1996; 87: 361–364. doi:10.1016/S0092-8674(00)81356-2
Lee J, Yang H, Georgescu M, Di Cristofano A, Maehama T, Shi Y, Dixon J, Pandolfi P, Pavletich N. Crystal structure of the PTEN tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999; 99: 323–334. doi:10.1016/S0092-8674(00)81663-3
Redfern R, Redfern D, Furgason M, Munson M, Ross A, Gericke A. PTEN phosphatase selectively binds phosphoinositides and undergoes structural changes. Biochemistry. 2008; 47: 2162–2171. doi:10.1021/bi702114w
Liaw D, Marsh D, Li J, Dahia P, Wang S, Zheng Z, Bose S, Call K, Tsou H, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997; 16: 64–67. doi:10.1038/ng0597-64
Tonks N, Cicirelli M, Diltz C, Krebs E, Fischer E. Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes. Mol Cell Biol. 1990; 10: 458–463. doi:10.1128/mcb.10.2.458
Maehama T, Dixon J. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273: 13375–13378. doi:10.1074/jbc.273.22.13375
Waite KA, Eng C. Protean PTEN: Form and function. Am J Hum Genet. 2002; 70: 829–844. doi:10.1086/340026
Georgescu M, Kirsch K, Kaloudis P, Yang H, Pavletich N, Hanafusa H. Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res. 2000; 60: 7033–7038.
Taylor B, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major J, Wilson M, Socci N, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010; 18: 11–22. doi:10.1016/j.ccr.2010.05.026
Grasso C, Wu Y, Robinson D, Cao X, Dhanasekaran S, Khan A, Quist M, Jing X, Lonigro J, Brenner J, Asangani I, Ateeq B, Chun S, Siddiqui J, Sam L, Anstett M, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012; 487: 239–243. doi:10.1038/nature11125
Barbieri C, Baca S, Lawrence M, Demichelis F, Blattner M, Theurillat J, White T, Stojanov P, Van Allen E, Stransky N, Nickerson E, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012; 44: 685–689. doi:10.1038/ng.2279
Phin S, Moore MW, Cotter PD. Genomic rearrangements of PTEN in prostate cancer. Front Oncol. 2013; 3: 240. doi:10.3389/fonc.2013.00240
Haverkamp J, Charbonneau B, Ratliff T. Prostate inflammation and its potential impact on prostate cancer: A current review. J Cell Biochem. 2008; 103: 1344–1353. doi:10.1002/jcb.21536
De Marzo A, Platz E, Sutcliffe S, Xu J, Gronberg H, Drake C, Nakai Y, Isaacs W, Nelson W. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7: 256–269. doi:10. 1038/nrc2090
Blum D, Koyama T, M’Koma A, Iturregui JM, Martinez-Ferrer M, Uwamariya C, Smith JA Jr, Clark PE, Bhowmick NA. Chemokine markers predict biochemical recurrence of prostate cancer following prostatectomy. Clin Cancer Res. 2008; 14: 7790–7797. doi:10.1158/1078-0432.CCR-08-1716
Tassidis H, Culig Z, Wingren A, Harkonen P. Role of the protein tyrosine phosphatase SHP-1 in Interleukin-6 regulation of prostate cancer cells. Prostate. 2010; 70: 1491–1500. doi:10.1002/pros.21184
Shariat S, Andrews B, Kattan M, Kim J, Wheeler T, Slawin K. Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis.Urology. 2001; 58: 1008–1015. doi:10.1016/S0090-4295(01)01405-4
Chung T, Yu J, Kong T, Spiotto M, Lin J. Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. Prostate. 2000; 42: 1–7. doi:10.1002/(sici)1097-0045(20000101)42:1<1::aid-pros1>3.0.co;2-y
Wen Z, Zhong Z, Darnell J. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995; 82: 241–250. doi:10.1016/0092-8674(95)90311-9
Abdulghani J, Gu L, Dagvadorg A, Lutz J, Leiby B, Bonuccelli G, Lisanti M, Zellweger T, Alanen K, Mirtti T, Visakorpi T, Bubendorf L, Nevalainen M. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008; 172: 1717–1728. doi:10.2353/ajpath.2008.071054
Blando J, Carbajal S, Abel E, Beltran L, Conti C, Fischer S, DiGiovanni J. Cooperation between Stat3 and Akt signaling leads to prostate tumor development in transgenic mice. Neoplasia. 2011; 13: 254–265. doi:10.1593/neo.101388
Schmid J, Birbach A. IkappaB kinase beta (IKKbeta/IKK2/IKBKB)–a key molecule in signaling to the transcription factor NF-kappaB. Cytokine Growth Factor Rev. 2008; 19: 157–165. doi:10.1016/j.cytogfr.2008.01.006
Shukla S, MacLennan G, Fu P, Patel J, Marengo S, Resnick M, Gupta S. Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. Neoplasia. 2004; 6: 390–400. doi:10.1593/neo.04112
Kong D, Li Y, Wang Z, Banerjee S, Sarkar F. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res. 2007; 67: 3310–3319. doi:10.1158/0008-5472.CAN-06-4277
Birbach A, Eisenbarth D, Kozakowski N, Ladenhauf E, Schmidt-Supprian M, Schmid J. Persistent inflammation leads to proliferative neoplasia and loss of smooth muscle cells in a prostate tumor model. Neoplasia. 2011; 13: 692–703. doi:10.1593/neo.11524
Osman I, Drobnjak M, Fazzari M, Ferrara J, Scher H, Cordon-Cardo C. Inactivation of the p53 pathway in prostate cancer: Impact on tumor progression. Clin Cancer Res. 1999; 5(8): 2082–2088.
Narasimhan M, Rose R, Karthikeyan M, Rathinavelu A. Detection of HDM2 and VEGF co-expression in cancer cell lines: Novel effect of HDM2 antisense treatment on VEGF expression. Life Sci. 2007; 81: 1362–1372. doi:10.1016/j.lfs.2007.08.029
Rose R, Narasimhan M, Rathinavelu A. Identification of HDM2 as a regulator of VEGF expression in cancer cells. Life Sci. 2008; 82: 1231–1241. doi:10.1016/j.lfs.2007.08.029
Ard P, Chatterjee C, Kunjibettu S, Adside L, Gralinski L, McMahon S. Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Mol Cell Biol. 2002; 22(16): 5650–5661. doi:10.1128/MCB.22.16.5650-5661.2002
Okamoto H, Fujishima F, Kamei T, et al. Murine double minute 2 predicts response of advanced esophageal squamous cell carcinoma to definitive chemoradiotherapy. BMC Cancer. 2015; 15: 208. doi:10.1186/s12885-015-1222-0
Udayakumar T, Hachem P, Ahmed M, Agrawal S, Pollack A. Antisense MDM2 enhances E2F1-induced apoptosis and the combination sensitizes androgen dependent and independent prostate cancer cells to radiation. Mol Cancer Res. 2008; 6(11): 1742–1754. doi:10.1158/1541-7786.MCR-08-0102
Wang G, Firoz E, Rose A. Blochin E, Christos P, Pollens D, Mazumdar M, Gerald W, Oddoux C, Lee P, Osman I. MDM2 expression and regulation in prostate cancer racial disparity. Int J Clin Exp Pathol. 2009; 2(4): 353–360.
Khor L, Desilvio M, Al-Saleem T, Hammond M, Grignon D, Sause W, Pilepich M, Okunieff P, Sandler H, Pollack A. Radiation therapy oncology group MDM2 as a predictor of prostate carcinoma outcome: An analysis of Radiation Therapy Oncology Group Protocol 8610. Cancer. 2005; 104: 962–967. doi:10.1002/cncr.21261
Leite K, Franco M, Srougi M, Nesrallah A, Bevilacqua R, Darini E, Carvalho C, Meirelles M, Santana I, Camara-Lopes L. Abnormal expression of MDM2 in prostate carcinoma. Mod Pathol. 2001; 5: 428–436. doi:10.1038/modpathol.3880330
Muthumani P, Alagarsamy K, Dhandayuthapani S, Venkatesan T, Rathinavelu A. Pro-angiogenic effects of MDM2 through HIF-1α and NF-ĸB mediated mechanisms in LNCaP prostate cancer cells. Mol Biol Rep. 2014; 41(8): 5533–5541. doi:10.1007/s11033-014-3430-0
Khor LY, Desilvio M, Al-Saleem T, Hammond M, Grignon D, Sause W, Pilepich M, Okunieff P, Sandler H, Pollack A. MDM2 as a predictor of prostate carcinoma outcome: An analysis of radiation therapy. Cancer. 2005; 104(5): 962–967. doi:10.1002/cncr.21261
Bond G, Hu W, Bond E, Robins H, Lutzker S, Arva N, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang S, Strong L, Lozano G, Levine A. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004; 119: 591–602. doi:10.1016/j.cell.2004.11.022
Yuan H, Gong A, Young CY. Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells. Carcinogenesis. 2005; 26: 793–801. doi:10.1093/carcin/bgi021
Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson J, Safe S. Ligand, cell and estrogen receptor subtype (alpha/beta)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem. 2000; 275: 5379–5387. doi:10.1074/jbc.275.8.5379
Bartel F, Jung J, Bohnke A, Gradhand E, Zeng K, Thomssen C, Hauptmann S. Both germ line and somatic genetics of the p53 pathway affect ovarian cancer incidence and survival. Clin Cancer Res. 2008; 14: 89–96. doi:10.1158/1078-0432.CCR-07-1192
Bond G, Hirshfield K, Kirchhoff T, Alexe G, Dond E, Robbins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 2006; 66: 5104–5110. doi:10.1158/0008-5472.CAN-06-0180
Bond G, Menin C, Bertorelle R, Alhopuro P, Aaltonen L, Levine A. MDM SNP309 accelerates colorectal tumour formation in women. J Med Genet. 2006; 43: 950–952. doi:10.1136/jmg.2006.043539
Lind H, Zienolddiny S, Ekstrom P, Skaug V, Haugen A. Association of a functional polymorphism in the promoter of the MDM2 gene with risk of non small cell lung cancer. Int J Cancer. 2006; 119: 718–721. doi:10.1002/ijc.21872
Alhopuro P, Ylisaukko-Oja S, Koskinen W, Bono P, Arola J, Jarvinen H, Mecklin J, Atula T, Kontio R, Makitie A, Suominen S, Leivo I, Vahteristo P, Aaltonen L, Aaltonen L. The MDM2 promoter polymorphism SNP309T-->G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck. J Med Genet. 2005; 42: 694–698. doi:10.1136/jmg.2005.031260
Yarden R, Friedman E, Metsuyanim S, Olender T, Ben-Asher E, Papa MZ. MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Breast Cancer Res Treat. 2008; 111: 497–504. doi:10.1007/s10549-007-9797-z
Thomasova D, Mulay SR, Bruns H, Anders H-J. p53-Independent roles of MDM2 in NF-kB signaling: Implications for cancer therapy, wound healing, and autoimmune diseases. Neoplasia. 2012; 14(12): 1097–1101. doi:10.1593/neo.121534
Tomlins S, Rhodes D, Perner S, Dhanasekaran S, Mehra R, Sun X, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005; 310: 644–648. doi:10.1126/science.1117679
Bugge T, Antalis T, Wu Q. Type II transmembrane serine proteases. J Biol Chem. 2009; 284(35): 23177–23181. doi:10.1074/jbc.R109.021006
Paoloni-Giacobino A, Chen H, Peitsch M, Rossier C, Antonarakis S. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane,LDLRA, and SRCR domains and maps to 21q22.3. Genomics. 1997; 44(3): 309–320. doi:10.1006/geno.1997.4845
Sreenath T, Dobi A, Srivastava S. Oncogenic activation of ERG: A predominant mechanism in prostate cancer. J Carcinog. 2011; 10: 37. doi:10.4103/1477-3163.91122
Carrere S, Verger A, Flourens A, Stehelin D, Duterque-Coquillaud M. Erg proteins, transcription factors of the Ets family, form homo heterodimers and ternary complexes via two distinct domains. Oncogene. 1998; 16(25): 3261–3268. doi:10.1038/sj.onc.1201868
Basuyaux J, Ferreira E, Stehelin D, Buttice G. The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner. J Biol Chem. 1997; 272(42): 26188–26195. doi:10.1074/jbc.272.42.26188
Perner S, Demichelis F, Beroukhim R, Schmidt F, Mosquera J, Setlur S, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006; 66(17): 8337–8341. doi:10.1158/0008-5472.CAN-06-1482
Cai C, Wang H, Xu Y, Chen S, Balk S. TMPRSS2: ERG gene expression in castration-resistant prostate cancer. Cancer Res. 2009; 69: 6027–6032. doi:10.1158/0008-5472.CAN-09-0395
Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, et al. TMPRSS2–ERG gene fusion prevalence and class are significantly different in prostate cancer of caucasian, African-American and Japanese patients. The Prostate. 2011; 71: 489–497. doi:10.1002/pros.21265
Hossain D, Bostwick D. Significance of the TMPRSS2:ERG gene fusion in prostate cancer. BJU Int. 2013; 111(5): 834–835. doi:10.1111/bju.12120
Mosquera J, Mehra R, Regan M, Perner S, Genega E, Bueti G, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res 2009; 15(14): 4706–4711. doi:10.1158/1078-0432.CCR-08-2927
Tomlins S, Laxman B, Varambally S, Cao X, Yu J. Role of the TMPRSS2–ERG gene fusion in prostate cancer. Neoplasia. 2008; 10: 177–188.
Nguyen P, Violette P, Chan S, Tanguay S, Kassouf W, Aprikian A, et al. A panel of TMPRSS2:ERG fusion transcript markers for urine-based prostate cancer detection with high specificity and sensitivity. Eur Urol. 2011; 59(3): 407–414. doi:10.1016/j.eururo.2010.11.026
Tu J, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen J. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: Frequency and transcript variant analysis by RT-PCR and FISH on paraffin embedded tissues. Mod Pathol. 2007; 20: 921–928. doi:10.1038/modpathol.3800903
Carver B, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009; 41(5): 619–624. doi:10.1038/ng.370
Brase J, Johannes M, Mannsperger H, Fälth M, Metzger J, Kacprzyk L, Andrasiuk T, Gade S, Meister M, Sirma H, Sauter G, Simon R, et al. TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer. 2011; 11: 507. doi:10.1186/1471-2407-11-507
Klezovitch O, Risk M, Coleman I, Lucas J, Null M, True L, et al. A causal role for ERG in neoplastic transformationof prostate epithelium. Proc Natl Acad Sci U S A. 2008; 105(6): 2105–2110. doi:10.1073/pnas.0711711105
Demichelis F, Fall K, Perner S, Andrén O, Schmidt F, Setlur S, et al. TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007; 26: 4596–4599. doi:10.1038/sj.onc.1210237
Kim J, Wu L, Zhao JC, Jin H-J, Yu J. TMPRSS2-ERG gene fusions induce prostate tumorigenesis through modulating microRNA miR-200c. Oncogene. 2014; 33(44): 5183–5192. doi:10.1038/onc.2013.461
Squire J. TMPRSS2-ERG and PTEN loss in prostate cancer. Nat Genet. 2009; 41: 509–510. doi:10.1038/ng0509-509
King J, Xu J, Wongvipat J, Hieronymus H, Carver B, Leung D, et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet. 2009; 41(5): 524–526. doi:10.1038/ng.371
Khani F, Mosquera J, Park K, Srivastava A, Tewari A, Mark R, et al. Differences in TMPRSS2-ERG gene fusion and SPINK1 overexpression in prostate cancer in African-American and Caucasian Men. J Urol. 2012; 187(4): e132. doi:10.1016/j.juro.2012.02.385
Laxman B, Tomlins S, Mehra R, Morris D, Wang L, Helgeson B, et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia. 2006; 8(10): 885–888. doi:10.1593/neo.06625
Tavukcu HH, Mangir N, Ozyurek M, Turkeri L. Preliminary results of noninvasive detection of TMPRSS2:ERG gene fusion in a cohort of patients with localized prostate cancer. Korean J Urol. 2013; 54(6): 359–363. doi:10.4111/kju.2013.54.6.359
Qu X, Randhawa G, Friedman C, et al. A novel four-color fluorescence in situ hybridization assay for the detection of TMPRSS2 and ERG rearrangements in prostate cancer. Cancer Genet. 2013; 206: 1–11. doi:10.016/j.cancergen.2012.12.004
Smit F, Salagierski M, Jannink S, Schalken J. High-resolution ERG-expression profiling on Genechip exon 1.0 ST arrays in primary and castration-resistant prostate cancer. BJU Int. 2013; 111: 836–842. doi:10.1111/bju.12119
Mostaghel E, Page S, Lin D, Fazli L, Coleman I, True L, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007; 67: 5033–5041. doi:10.1158/0008-5472.can-06-3332
Reig Ò, Marín-Aguilera M, Carrera G, Jiménez N, Paré L, García-Recio S, Gaba L, Pereira M, Fernández P, Prat A, Mellado B. TMPRSS2-ERG in blood and docetaxel resistance in metastatic castration-resistant prostate cancer. Eur Urol. 2016; S0302–2838 (16): 00212–00218. doi:10.1016/j.eururo.2016.02.034