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The physiopathological evolution
of prostate cancer
Antonello Di Paolo
Dipartimento di Medicina Clinica e Sperimentale
Università di Pisa
Androgens are key players in prostate
cancer proliferation
Selective pharmacological pressure and
adaptation in prostate cancer
Selective pressure
Adaptation
Knudsen KE, Penning TM. Trends Endocrinol Metab 2010; 21: 315-324
CRPC is not androgen independent
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Androgen-dependent signaling mediates prostate cancer growth
despite castrate levels of serum testosterone
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Mechanisms:
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Increased androgen uptake
Increased AR ligand synthesis
Receptor overexpression/amplification
AR mutations (eg, hypersensitivity)
Ligand-independent AR activation
Sharifi N, et al. J Investig Med. 2010;58:938-944. Dutt SS, et al. Future Oncol. 2009;5:1403-1413.
CRPC is not androgen independent
Knudsen KE, Penning TM. Trends Endocrinol Metab 2010; 21: 315-324
AR gene
PTEN gene
Tumor suppressor genes
Grasso et al. Nature. 2012; 487: 239–243
AR mutation and gain of function
LNCaP
LNCaP-hr
M.C. privo di
androgeni
LNCaP-cDx
Bicalutamide
Bicalutamide
no
1 μM
Hara et al. Cancer Res 2012; 63: 149-153
AR gene mutations
Transactivation assays showed that bicalutamide worked as an
agonist for both W741C and W741L mutant ARs
Hara et al. Cancer Res 2012; 63: 149-153
Alternative splicing of AR gene
Hu et al. Cancer Res 2009; 69: 16-22
High gene expression of AR splicing
variants in hormone-refractory PCa
HRPC, hormone-refractory PCa
AR
AR-V1
AR-V7
11x
22x
20x
Hu et al. Cancer Res 2009; 69: 16-22
Post-translational modifications of AR
Gioeli & Paschal. Mol Cell Endocrinol 2012; 352: 70–78
Post-translational modifications of AR
Gioeli & Paschal. Mol Cell Endocrinol 2012; 352: 70–78
Cell cycle regulation from G0 to G1-S
Mitogens
Ras/Raf/MAPK
D-type cyclins
CDK4/6
CDK4/6-cyclin D
CDK2
G1-S transition
Cyclin E
CDK2-cyclin E
Phosphorylation of proteins involved in
histone modification, DNA replication and
repair, centrosome duplication and
maturation
pRB/p107/p130
DP(1,2)
E2Fn-DPn
E2F(1-6)
Recruitment of repressor complexes such
as histone deacetylases and chromosomal
remodeling SWI/SNF complexes
“…cyclin D1b was found to modulate the
expression of a large transcriptional network that
cooperates with androgen receptor (AR) signaling
to enhance tumor cell growth and invasive
potential. Notably, cyclin D1b promoted ARdependent activation of genes associated with
metastatic phenotypes. Further exploration
determined that transcriptional induction of SNAI2
(Slug) was essential for cyclin D1b–mediated
proliferative and invasive properties, implicating
Slug as a critical driver of disease progression.
Importantly, cyclin D1b expression highly
correlated with that of Slug in clinical samples of
advanced disease…”
Augello et al. J Clin Invest. 2013;123(1):493–508
Intracrine androgen synthesis
Cancer Res 2006;66:2815-2825
“…the dominant route of DHT synthesis in CRPC bypasses testosterone,
and instead requires 5α-reduction of androstenedione by SRD5A1 to 5αandrostanedione, which is then converted to DHT…”
Androstenedione sustains PCa xenograft
growth in castrated mice
Increased bioavailability of precursors
-34T>C
A1 [ T ] normal transcription activity
A2 [ C ] increased transcription activity
Median overall survival:
A1, 7.6 years vs. A2, 8.9 years
(p<0.040 by log-rank test)
Hamada et al. Urology 2007; 70: 217-220
Increased cellular uptake in PCa
“The superfamily of organic anion-transporting
polypeptides (OATP), encoded by SLCO
genes, mediates the … uptake of various
endogenous compounds and drugs into
cells… SLCO2B1 and SLCO1B3 have been
shown to be involved in the steroid hormone
uptake. SLCO2B1 … mediates the transport of
steroid conjugates, such as DHEAS and
estrone-3-sulfate. SLCO1B3 [is] involved in the
uptake of several hormones including T”
J Clin Oncol 2011; 29: 2565-2573
SLCO2B1 SNPs are associated with increased
gene expression and cell growth in vitro
Yang et al. J Clin Oncol 2011; 29: 2565-2573
SLCO2B1 SNPs and TTP
Yang et al. J Clin Oncol 2011; 29: 2565-2573
SLCO2B1-SLCO1B3 SNPs and TTP
Yang et al. J Clin Oncol 2011; 29: 2565-2573
Stem cells in prostate cancer
Mimeault & Batra. Biochim Biophys Acta 2011; 1816: 25–37
Epigenetics in prostate cancer
Shen & Pili. Cancer J 2008;14:46-53
Epigenetics in prostate cancer
Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in
prostate development and function, as well as malignant transformation.
AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression.
AR as a globally acting transcriptional repressor.
This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb
group protein EZH2 and repressive chromatin remodeling.
In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3
and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of
which maintains the undifferentiated state.
Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem
cell–like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected
role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive
signaling, resulting in cancerous dedifferentiation.
Zhao et al. Genome Res 2012; 22: 322-331
AR directly regulates a large number of
target genes
Zhao et al. Genome Res 2012; 22: 322-331
Expression of steroidogenic enzymes in
castration-resistant metastases versus primary prostate
Montgomery et al. Cancer Res 2008; 68: 4447-4454
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Mean tissue androgen levels in castration-resistant
metastases from anorchid patients versus primary
prostate tissues from eugonadal men
Montgomery et al. Cancer Res 2008; 68: 4447-4454
Conclusion
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Advanced prostate cancer is neither hormone refractory nor
androgen independent and remains nuclear steroid receptor
driven
Several adaptive pathways may sustain cancer growth
Androgen receptor acts as a transcriptional repressor, which
maintains a stem cell-like undifferentiated state
The complex and redundant biochemical network behind CRPC
may offer several “drugable” targets and biomarkers for patients’
stratification