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The Androgen
Receptor Role in Hormone Refractory Prostate Cancer
A Functioning
Androgen Receptor Is Essential For Progression Of "Androgen-Refractory"
Prostate Cancer.
A pivotal article was
published in Nature Medicine, January 2004, by the Sawyers group, a
consortium of researchers principally at UCLA (including Robert Vessella,
University of Washington) entitled "Molecular determinants of resistance
to antiandrogen therapy." This investigation showcases a breathtakingly
elegant display of their command of the fullest range of the techniques
of investigative molecular biology in the service of analyzing the role
of the androgen receptor in "androgen refractory" prostate cancer. Their
proficiency is on par with Yo Yo Ma performing a Bach Suite. A review of
the article in detail is warranted, and is best begun by quoting the
opening of their abstract:"Using microarray-based profiling of isogenic
prostate cancer xenograph models, we found that a modest increase in
andgrogen receptor mRNA was the only [emphasis mine]
change consistently associated with the development of resistance to
antiandrogen therapy. This increase in androgen receptor mRNA and
protein was both necessary and sufficient to convert prostate cancer
growth from a hormone-sensitive to a hormone-refractory stage, and was
dependent on a functional ligand-binding domain". They established that
this transition develops in a setting of low levels of residual androgen
[i.e. post Lupron or castration] and is associated with alteration of
the normal response to antagonists [i.e. bicalutamide]. The article
proceeded with tight logic to support the authors' thesis.
1) By
examining gene expression profiles of related pairs of
androgen-sensitive and androgen-refractory prostate cancer cells by
employing 12,559 comparisons ("probe sets") and augmenting the findings
by immunoblot data, they established that the androgen refractory cells
displayed three to five times the amount of androgen receptors (AR)
compared to the androgen sensitive cells from which the refractory cells
originated.
2) Next,
the researchers demonstrated that increased androgen receptors cause
tumor progression by showing that cells with a three fold increase in
androgen receptors grew > 50% faster in castrated animals than
appropriate comparison androgen sensitive cells. And reciprocally, they
demonstrated that the AR was required for this progression. When the
expression of the androgen receptor gene was shut down by virtue of mRNA
signal destruction by "small hairpin interfering RNAs" tumor growth was
slowed. Conclusion: "a modest increase in receptor concentration permits
the receptor to function despite the lower levels of androgen in
castrated [animals]."
3) At
this point the investigation took an interesting and instructive turn.
They demonstrated that "higher androgen receptor levels convert
antagonist [i.e. bicalutamide] to agonist". At the gene promoter site
where the AR initiates gene transcription of the genes under androgen
control, the AR must be joined by a bevy of co-activators and
co-repressors in order that transcription may proceed, and the balance
between these co-factors is crucial to the outcome. (If the
transcription complex team were playing football they would be penalized
for "piling on".) Bicalutamide normally functions as a repressor in this
transcription complex, but the research showed that in a setting of a
modest increased AR, bicalutamide becomes an activator.
What implications
can be drawn from these findings if they are confirmed? First, since a
functioning AR continues to be pivotal in the progression of "hormone
refractory" disease, there is a need for the development of new
antiandrogens which can inactivate the androgen receptor DNA binding
domain, crucial for the activation of the many genes under androgen
control. Secondly, since the activated AR must be chaperoned from
cytoplasm to nucleus by "nuclear localization signals", these signals
themselves could be a useful target for therapeutic intervention so that
the cytoplasmic/nuclear transition could be prevented. And finally (see
below) it might be possible to target the AR gene itself, prevent its
expression, and interrupt the activation of the many genes under
androgen control. This a remarkable article well worth reading.
Bottom Line:
There is much work still to be accomplished in preventing AR function in
"androgen refractory" prostate cancer.
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