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JOHN T. ISAACS
The Sidney Kimmel Comprehensive Cancer Center (I.V.L., A.M.D., J.T.I.), the Department of Pathology (A.M.D.), the
Cellular and Molecular Graduate Program (I.V.L., J.T.I.), and the Brady Urological Institute, The Department of Urology
(A.M.D., J.T.I.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231
Abbreviations: AR, Androgen receptor; ARE, androgen response element; BM, basement membrane; DHT, dihydrotestosterone; FGF, fibroblast growth factor; GST, glutathione-S-transferase; GSTP1, GST ;
HGF, hepatocyte growth factor; HGPIN, high-grade PIN; hK2, human
glandular kallikrein-2; Hsp, heat shock protein; LBD, ligand binding
domain; NE, neuroendocrine; PIA, proliferative inflammatory atrophy;
PIN, prostatic intraepithelial neoplasia; PKA, protein kinase A; PSA,
prostate-specific antigen; PSCA, prostate stem cell antigen; PSMA, prostate-specific membrane antigen; STAT, signal transducers and activators
of transcription; VEGF, vascular endothelial growth factor.
2972
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sion of chromogranin A, serotonin, and neuron-specific enolase, but not AR (7). Functionally, the epithelium is composed
of multiple stem cell units (8 14) (Fig. 2). In an individual
stem cell unit, the stem cell that has the capacity for unlimited
self-renewal characteristically expresses 21-integrins (15)
but only rarely proliferates to provide progeny that differentiate to become either transit-amplifying or NE cells (10,
11). The stem and the majority of the transit-amplifying cells
are believed to be located in the basal epithelial layer (Figs.
1 and 2). A subset of basal cells represent stem cells, and the
remainder represent transit-amplifying cells.
Basal cells express prostate stem cell antigen (PSCA), the
p53-related p63 protein, c-Met, the plasma membrane receptor for hepatocyte growth factor (HGF), and the prosurvival
protein bcl-2 (16 19). A subset of these cells shows proliferative activity as evidenced by positive staining for Ki-67,
and these presumed transit-amplifying cells, which are also
referred to as intermediate cells in the prostate, either do not
express AR or express it at very low levels (20, 21). During
the hierarchical expansion of prostatic epithelium cells, a
minority of stem cell progeny differentiate into NE cells that
secrete neuroendocrine peptides like bombesin, calcitonin,
and PTH-related peptide (22). The majority of the stem cell
progeny become transit-amplifying cells that eventually terminally differentiate into mature secretory luminal cells that
are nonproliferative and positive for AR and p27Kip1cyclindependent kinase inhibitor (20, 21, 23) (Fig. 2). Because of this
hierarchical expansion, these nonproliferating AR/p27Kip1positive secretory luminal cells are quantitatively the major
subtype of epithelial cells present in the normal prostate.
These AR/p27Kip1-positive secretory luminal cells also express the prostate-specific differentiation markers, prostatic
specific acid phosphatase, prostate-specific antigen (PSA),
NKX 3.1, human glandular kallikrein-2 (hK2), prostatespecific membrane antigen (PSMA), and PSCA, as well as
vascular endothelial growth factor (VEGF) (2529). The transcriptional expression of these prostate-specific differentiation marker genes is enhanced by occupancy of the AR with
physiological androgen [dihydrotestosterone (DHT)] and
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2974
FIG. 2. Stem cell model of prostatic epithelial cell compartmentalization. The prostate gland consists of a number of stem cell units that arise
from one stem cell. Such a stem cell is located in the basal epithelial layer of the prostate and, upon division, gives rise to a population of
transit-amplifying cells. The latter divide in the basal layer, and a fraction of them differentiate and move into the secretory luminal epithelial
layer. As transit-amplifying cells differentiate and move into a secretory luminal layer from the basal layer, they acquire expression of a number
of genetic markers, as indicated. **, Low-level retention of expression by a subset of transit-amplifying (i.e. intermediate) cells; , expression
of marker; , lack of detectable expression of marker.
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the tissue VEGF levels results in the activation of the apoptotic death of a subset of stromal endothelial cells, reducing
tissue blood flow (48).
Although secretory luminal cells undergo apoptosis after
androgen ablation, the basal stem and transit-amplifying
cells do not (49). A possible explanation for this observation
is that prostatic stromal cells express HGF (18). HGF expression by these stromal cells is not regulated by androgen
occupancy of the AR in these stromal cells (50). Basal stem
and transit-amplifying cells constitutively express c-MET,
the plasma membrane cognate receptor for HGF, whereas
secretory luminal cells do not (18). Such c-MET signaling is
inhibitory for basal cell apoptosis and proliferation (18).
Thus, after androgen ablation, the prostatic stromal cells
continue to supply adequate levels of HGF to bind to and
induce signaling by the c-MET receptors of the basal cells,
thus both blocking activation of apoptosis and inhibiting
proliferation of these basal cells (18).
AR signaling in prostate epithelium functions as a growth
suppressor and differentiation inducer
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2976
FIG. 3. New model for prostatic carcinogenesis. A number of molecular and morphological changes take place as normal prostatic epithelium
proceeds to form invasive incurable prostatic carcinoma. Such changes are associated and could be caused by inflammation, diet, and other
environmental stresses. Inherent genetic factors are also playing an important role in cancer initiation and progression.
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ARs are ligand-dependent zinc finger DNA binding proteins whose genomic binding coordinates formation of transcriptional complexes at the regulatory elements of targeted
genes. The AR gene is located on the long arm of the X
chromosome (i.e. Xq11.2) and encodes a protein with three
critical domains: 1) an N-terminal domain involved in homotypic dimerization and binding with other transcriptional
coactivator or corepressor proteins; 2) a DNA binding domain with two zinc finger binding motifs and hinge region;
and 3) a C-terminal steroid ligand binding domain (LBD),
which is also involved in homotypic dimerization and coactivation binding (Fig. 4). This latter C-terminal LBD domain is also where 90-kDa heat shock protein (i.e. Hsp-90)
dimers bind to stabilize the AR protein during its folding,
subsequent to its synthesis (83). Specific interaction with
androgenic ligands results in the conformational activation
of AR. This allows the dissociation of the Hsp-90 dimer
proteins and thus the binding and dimerization of the occupied AR ; Ref. (84) to androgen-response elements present
in the promoter and enhancer regions in AR-regulated genes
(27, 29 32).
This initial genomic AR binding allows further binding to
specific regions of the bound AR by additional nuclear proteins (i.e. transcriptional coactivator proteins like SRC-1,
ARA 70, etc., and general transcription factors like TFIIF and
H) to produce transcriptional complexes that can activate or
repress specific gene expression (85). For activation, formation of an active transcriptional complex is required, resulting in site-directed chromatin remodeling via histone acetylation and methylation that enhances target gene expression
(85 89) (Fig. 5). SRC-1 is a member of the p160 transcriptional
coactivator gene family that includes SRC-1, TIF2 (also
termed GRIP-1 and SRC-2), and p/CIP (also termed RAC3,
ACTR, AIBI, and SRC-3) (89). Cell-free in vitro transcription
and in vivo experiments have indicated that the SRC-1 family
members enhance AR-dependent transactivation of nuclear
genes (85 89), the mechanism for such enhancement involves binding of p160 proteins to the DNA bound AR (Fig.
5). This allows the p160 to acetylate histones via its histone
acetyltransferase activity. Additional coactivators with histone acetyltransferase activity such as CBP, p300, or p/CAF
also bind to the p160/AR complex. This results in chromatin
remodeling and additional binding of general transcription
factors such as TBp and TIFIIB with the AR coactivation
complexes (85 89) (Fig. 5).
On the basis of this overview of normal AR signaling, the
AR-signaling cascade in prostate cancer cells can become
constitutively active (i.e. independent of circulating androgen) via several genetic and epigenetic mechanisms. With
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2978
domain of the AR. C-terminal AR mutations have been documented to allow new physiological endogenous nonandrogenic steroids (e.g. estrogens, glucocorticoids, and progestins) to bind to the LBD of AR-inducing formation of
functional transcriptional complexes (90, 91).
Additional epigenetic mechanisms also can allow such
productive formation of constitutive AR transcriptional complexes without androgen ligand binding. For example, it has
been documented that expression of AR at relatively low
levels results in strong ligand-dependent activation, whereas
high levels of AR lead to androgen-independent transcriptional activation (92). Because approximately 90% of androgen ablation failing prostate cancers overexpress AR (7577),
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this could provide a mechanism for their resistance. In addition, experimental studies have demonstrated that there is
cross talk between the AR and the signaling pathway induced by costimulation of pathways involving protein kinase A (PKA) and/or certain peptide growth factors (9397).
These studies have demonstrated that when AR is not expressed, signaling induced by PKA or certain peptide growth
factors (e.g. IL-6) is unable to stimulate the transcription of
prostate-specific marker genes like PSA, by androgen-independent prostate cancer cells. In contrast, when AR is expressed ectopically, PKA and IL-6 can now induce the expression of these marker genes constitutively even in an
androgen-depleted environment (93, 9598).
For this latter effect of ligand-independent AR signaling by
IL-6, physical interaction between N-terminal domain of AR
with SRC-1 coactivator is critical (98). Although such physical AR/SRC-1 interaction does not require phosphorylation
of SRC-1 or ligand binding, transcriptional signaling by the
AR/SRC-1 complex does require phosphorylation of SRC-1
by MAPK activated in the signaling cascade initiated by IL-6
binding to its plasma membrane receptor expressed on prostate cancer cells (98). Besides activating the MAPK pathways,
such IL-6 binding to its receptor activates the janus-kinasesignal transducers and activators of transcription (STAT)-3
pathway (99, 100). This activation results in activated januskinase phosphorylating STAT-3 proteins in the cytoplasm.
Once phosphorylated, STAT-3 dimerizes and then is transported into the nucleus. Dimerized STAT-3 can bind ligandfree AR, allowing the complex to be translocated into the
nucleus where it can induce transcription (99). Such STAT3/AR activation allows resistance to androgen ablation by
AR-expressing prostate cancer cells both in vitro and in vivo
(100).
Rational drug development based on gain of function
changes in AR signaling pathways
These previously discussed genetic and epigenetic mechanisms provide a framework for rational drug development
for androgen ablation failing prostate cancer cells. The most
obvious way to prevent the gain of function AR-dependent
signaling is to prevent the expression of the AR protein itself.
Presently, this can be achieved experimentally by a variety
of molecular (e.g. antisense, small interfering RNA, Hammerhead ribozyme) (80 82) and small molecule approaches
(e.g. HSP-90 antagonists) (101). Although the nucleic acidbased approaches are potentially more specific for AR expression down-regulation, they are presently harder to develop clinically. The small molecule approaches have
identified that agents like geldanamycin can bind to the
Hsp-90/AR complex enhancing the degradation of the AR
protein by proteasomal targeting (101). Because Hsp-90
chaperones a series of additional proteins other than AR (e.g.
raf, Akt, etc.), such Hsp-90 antagonists may suffer from the
problem of their therapeutic index because they will downregulate more than just AR in normal as well as cancer cells.
An alternative approach is not to down-regulate AR directly but instead to inhibit the ability of AR to interact and
bind with the critical coactivators required for the formation
of productive transcriptional complexes. Because these are
malignancy-acquired gain of function interactions, these interactions should be unique to androgen ablation-resistant
prostatic cancer cells, and thus inhibiting these interactions
should not produce host toxicity. To develop such inhibitors,
in vitro cell line model systems are critical because they allow
for both mechanistic studies for therapeutic target discovery
and rapid throughput screening to identify compounds for
drug development. It has been assumed that understanding
the interaction of the specific coactivators with AR at these
prostate-specific differentiation genes (i.e. PSA, hK2, PSMA)
in these model systems would also provide an understanding of the mechanisms whereby AR interactions regulate the
genes for proliferation and survival of malignant prostate
cells.
In a significant number of such model cell lines, however,
there is a dissociation between androgen-responsive regulation of malignant growth vs. regulation of the expression
of prostate-specific markers PSA and hK2 (102). These results
emphasize that tumor growth and the expression of the
differentiation-specific marker genes are independently regulated molecular events even if they share a requirement for
androgen and/or AR function. Additional independent
mechanisms can occur in prostate cancer cells for regulation
of expression for even the highly related PSA and hK2 genes
(102). Thus, the use of prostate-specific differentiation
marker gene regulation as surrogate model systems for clarifying AR signals of proliferation and survival of prostate
cancer is highly problematic. Future studies need to clarify
the mechanisms for androgen ligand-independent/ARdependent regulation of the genes that directly affect the
proliferation and survival of androgen ablation resistant
prostate cancer cells.
Conclusions
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2980
Acknowledgments
We appreciate the secretarial support of Dorothea K. Stieff and thank
Don Vindivich for help in preparation of the figures.
Received December 26, 2002. Accepted April 4, 2003.
Address all correspondence and requests for reprints to: John T.
Isaacs, Ph.D., Johns Hopkins Oncology, 1650 Orleans Street, Cancer
Research Building 1M44, Baltimore, Maryland 21231-1000. E-mail:
isaacjo@jhmi.edu.
This work was supported by National Institutes of Health Grant
DK52645.
References
1. Isaacs JT 1983 Prostatic structure and function in relation to the etiology of
prostatic cancer. Prostate 4:351366
2. Carter B, Pianpadosi S, Isaacs JT 1990 Clinical evidence for and implications
of the multistep development of prostate cancer. J Urol 143:742746
3. Berges RR, Vukanovic J, Epstein JI, CarMichel M, Cisek L, Johnson DE,
Veltri RW, Walsh PC, Isaacs JT 1995 Implication of the cell kinetic changes
during the progression of human prostatic cancer. Clin Cancer Res 1:473 480
4. Isaacs JT 1994 Role of androgens in prostatic cancer. Vitam Horm 49:433502
5. Prostate Cancer Trialists Collaborative Group 1995 Maximum androgen
blockade in advances prostate cancer: an overview of 22 randomized trials
with 3238 deaths in 5710 patients. Lancet 346:265269
6. Gottlieb B, Vasiliou DM, Lumbroso R, Beitel LK, Pinsky L, Trifiro MA 1999
Analysis of exon 1 mutations in the androgen receptor gene. Hum Mutat
14:527539
7. Bonkhoff H 1998 Neuroendocrine cells in benign and malignant prostate
tissue: morphogenesis, proliferation, and androgen receptor status. Prostate
Suppl 8:18 22
8. Isaacs JT 1987 Control of cell proliferation and cell death in the normal and
neoplastic prostate: a stem cell model. In: Rogers CH, Coffey DS, Cunha G,
Grayhack J, Hinman F, Horton R, eds. Benign prostatic hyperplasia. Report
No. INH 87-2881, Department of Health and Human Services, National Institutes of Health, Bethesda, MD, p 8594
9. Isaacs JT, Coffey DS 1989 Etiology and disease process of benign prostatic
hyperplasia. Prostate Suppl 2:3350
10. Bonkhoff H, Stein U, Remberger K 1994 Multidirectional differentiation in
the normal, hyperplastic, and neoplastic human prostate: simultaneous demonstration of cell-specific epithelial markers. Hum Pathol 25:42 46
11. Bonkhoff H, Remberger K 1996 Differentiation pathways and histogenetic
aspects of normal and abnormal prostatic growtha stem cell model. Prostate
28:98 106
12. Robinson EJ, Neal DE, Collins AT 1998 Basal cells are progenitors of luminal
cells in primary cultures of differentiating human prostate epithelium. Prostate 37:149 160
13. Van Leenders G, Dijkman H, Hulsbergen-van de Kaa C, Ruiter D, Schalken
J 2000 Demonstration of intermediate cells during human prostate epithelial
differentiation in situ and in vitro using triple-staining confocal scanning
microscopy. Lab Invest 80:12511258
14. Hudson DL, OHare M, Watt FM, Master JR 2000 Proliferative heterogeneity
in the human prostate: evidence for epithelial stem cells. Lab Invest 80:1243
1250
15. Collins AT, Habib FK, Maitland NJ, Neal DE 2001 Identification and isolation of human prostate epithelial stem cells based on 21-integrin expression. J Cell Sci 114:38653872
16. Watabe T, Lin M, Ide H, Donjacour AA, Cunha GR, Witte ON, Reiter RE
2002 Growth, regeneration, and tumorigenesis of the prostate activates the
PSCA promoter. Proc Natl Acad Sci USA 99:401 406
17. Signoretti, S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, Yang A,
Montironi R, McKeon F, Loda M 2000 p63 Is a prostate basal cell marker and
is required for prostate development. Am J Pathol 157:1769 1775
18. Gmyrek GA, Walburg M, Webb CP, Yu HM, You X, Vaughan ED, Van
Woude GF, Knudsen BS 2001 Normal and malignant prostate epithelial cells
differ in their response to hepatocyte growth factor/scatter factor. Am J
Pathol 159:579 590
19. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LWK, Hsieh
JT, Tu SM, Campbell ML 1992 Expression of the protooncogene Bcl-2 in the
prostate and association with emergence of androgen-independent prostate
cancer. Cancer Res 52:6940 6944
20. Bonkhoff H, Stein U, Remberger K 1994 The proliferative function of basal
cells in the normal and hyperplastic human prostate. Prostate 24:114 118
21. Bonkhoff H, Fixemer T, Remberger K 1998 Relation between Bcl-2, cell
proliferation, and the androgen receptor status in prostate tissue and precursors of prostate cancer. Prostate 34:251258
22. Rumpold H, Heinrich E, Untergasser G, Hermann M, Pfister G, Plas E,
Berger P 2002 Neuroendocrine differentiation of human prostatic primary
epithelial cells in vitro. Prostate 53:101108
23. De Marzo AM, Meeker AK, Epstein JI, Coffey DS 1998 Prostate stem cell
compartments: expression of the cell cycle inhibitor p27kip1 in normal, hyperplastic, and neoplastic cells. Am J Pathol 153:911919
24. Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Young CY,
Klee GG, Tindall DJ, Bostwick DG 1997 Human glandular kallikrein 2 (hK2)
expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel
prostate cancer marker. Urology 49:857 862
25. Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck MR, Vocke
CD, Linehan WM, Ferretti JA 2001 Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium. J Urol 165:1329 1334
26. Liu H, Moy P, Kim S, Xia Y, Rajasekaran A, Navarro V, Knudsen B, Bander
NH 1997 Monoclonal antibodies to the extracellular domain of prostatespecific membrane antigen also react with tumor vascular endothelium. Cancer Res 57:3629 3634
27. Jain A, Lam A, Vivanco I, Carey MF, Reiter RE 2002 Identification of an
androgen-dependent enhancer within the prostate stem cell antigen gene.
Mol Endocrinol 16:23232337
28. Joseph IB, Nelson JB, Denmeade SR, Isaacs JT 1997 Androgens regulate
vascular endothelial growth factor content in normal and malignant prostatic
tissue. Clin Cancer Res 3:25072511
29. Schuur ER, Henderson GA, Kmetec LA, Miller JD, Lamparski HG, Henderson DR 1996 Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 271:70437051
30. Watt F, Martorana A, Brookes DE, Ho T, Kingsley E, OKeefe DS, Russell
PJ, Heston WD, Molloy PL 2001 A tissue-specific enhancer of the prostatespecific membrane antigen gene, FOLH1. Genomics 73:243254
31. Zelivianski S, Igawa T, Lim S, Taylor R, Lin M 2002 Identification and
characterization of regulatory elements of the human prostatic acid phosphatase promoter. Oncogene 21:3696 3705
32. Mitchell SH, Murtha PE, Zhang S, Zhu W, Young CYF 2000 An androgen
response element mediates LNCaP cell dependent androgen induction of the
hK2 gene. Mol Cell Endocrinol 168:89 99
33. Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ,
Sugimura Y 1987 The endocrinology and developmental biology of the prostate. Endocr Rev 8:338 362
34. Hayward SW, Del Buono R, Deshpande N, Hall PA 1992 A functional model
of adult human prostate epithelium: the role of androgens and stroma in
architectural organization and the maintenance of differentiated secretory
function. J Cell Sci 102:361372
35. Kurita T, Wany YZ, Donjacour AA, Zhao C, Lydon JP, OMalley BW, Isaacs
JT, Dahiya R, Cunha GR 2001 Paracrine regulation of apoptosis by steroid
hormones in the male and female reproductive system. Cell Death Differ
8:192200
36. Bonkhoff H, Stein U, Aumuller G, Remberger K 1996 Differential expression
of 5 -reductase isoenzymes in the human prostate and prostatic carcinomas.
Prostate 29:261267
37. Gerdes MJ, Larsen M, McBride L, Dang TD, Lu B, Rowley DR 1998 Localization of transforming growth factor-1 and type II receptor in developing
normal human prostate and carcinoma tissues. J Histochem Cytochem 46:
379 388
38. Peehl DM, Sellers RG 1997 Induction of smooth muscle cell phenotype in
cultured human prostatic stromal cells. Exp Cell Res 232:208 215
39. Yang G, Timme TL, Park SH, Thompson TC 1997 Transforming growth
factor 1 transduced mouse prostate reconstitutions. I. Induction of neuronal
phenotypes. Prostate 33:151156
40. Kyprianou N, Isaacs JT 1989 Expression of transforming growth factor- in
the rat ventral prostate during castration-induced programmed cell death.
Mol Endocrinol 3:15151522
41. Wikstrom P, Westin P, Stattin P, Damber JE, Bergh A 1999 Early castrationinduced upregulation of transforming growth factor 1 and its receptors is
associated with tumor cell apoptosis and a major decline in serum prostatespecific antigen in prostate cancer patients. Prostate 38:268 277
42. Lu W, Luo Y, Kan M, McKeehan WL 1999 Fibroblast growth factor-10. A
second candidate stromal to epithelial cell andromedin in prostate. J Biol
Chem 274:1282712834
43. Planz B, Aretz HT, Wang Q, Tabatabaei S, Kirley SD, Lin CW, McDougal
WS 1999 Immunolocalization of the keratinocyte growth factor in benign and
neoplastic human prostate and its relation to androgen receptor. Prostate
41:233242
44. Martikainen P, Kyprianou N, Isaacs JT 1990 Effect of transforming growth
factor-1 on proliferation and death of rat prostatic cells. Endocrinology
127:29632968
45. Denmeade SR, Lin XS, Isaacs JT 1996 Role of programmed (apoptotic) cell
death during the progression and therapy of prostate cancer. Prostate 28:
251265
46. Kyprianou N, Isaacs JT 1988 Activation of programmed cell death in the rat
ventral prostate after castration. Endocrinology 122:552562
47. Kyprianou N, English HF, Isaacs JT 1988 Activation of a Ca2-Mg2dependent endonuclease as an early event in castration-induced prostatic cell
death. Prostate 13:103117
48. Lissbrant IF, Lissbrant E, Damber JE, Bergh A 2001 Blood vessels are reg-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 September 2014. at 01:29 For personal use only. No other uses without permission. . All rights reserved.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 September 2014. at 01:29 For personal use only. No other uses without permission. . All rights reserved.
2982
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
kinase inhibitor p21 gene: role of androgen receptor and transcription factor
Sp1 complex. Mol Endocrinol 14:753760
Gnanapragasam VJ, Robson CN, Neal DE, Leung HY 2002 Regulation of
FGF8 expression by the androgen receptor in human prostate cancer. Oncogene 21:5069 5080
Agus DB, Cordon-Cardo C, Fox W, Drobnjak M, Koff A, Golde DW, Scher
HI 1999 Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst
91:1869 1876
Valve EM, Nevalainen MT, Nurmi MJ, Laato MK, Martikainen PM,
Harkonen PL 2001 Increased expression of FGF-8 isoforms and FGF receptors
in human premalignant prostatic intraepithelial neoplasia lesions and prostate cancer. Lab Invest 81:815 826
Song Z, Wu X, Powell WC, Cardiff RD, Cohen MD, Tin RT, Matusik RJ,
Miller GJ, Roy-Burman P 2002 Fibroblast growth factor 8 isoform B overexpression in prostate epithelium: a new mouse model for prostatic intraepithelial neoplasia. Cancer Res 62:5096 5105
Aaltomaa S, Lipponen P, Eskelinen M, Ala-Opas M, Kosma VM 1999
Prognostic value and expression of p21 (waf1/cip1) protein in prostate cancer. Prostate 39:8 15
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