Institute of Medical Technology, University of Tampere
and Tampere University Hospital FIN-33101, Tampere,
Finland tapio.visakorpi@uta.fi
Expression of different pp32 gene family members and cross-talk
between the HER-2/neu and androgen receptor signaling pathways may be involved
in prostate cancer development (pages 275−285).
Prostate cancer is the second leading cause of death among men in Western
countries. In this issue of Nature Medicine, two papers identify different
molecular mechanisms that may be involved in prostate cancer development and
progression. On page 275 Kadkol et al.1 demonstrate that pp32 expression is altered in prostate cancer—benign
prostate tissue expresses pp32 whereas carcinomas express the variants pp32r1
and pp32r2. In a second paper on page 280, Craft
et al.2 show that the HER-2/neu tyrosine kinase modulates
the response of the androgen receptor (AR) to low doses of androgens, suggesting
that kinase activity might be important in the development of androgen-independent
prostate cancer.
Last year Kadkol and co-workers3 reported that pp32 is overexpressed
in malignant prostate tissue even though this nuclear phosphoprotein is a
tumor suppressor. Using cleavase fragment length polymorphism analysis and
sequencing, they now show that prostate cancer cell lines as well as prostate
tumors express the variants pp32r1 and pp32r2 and not pp32 itself. The transcripts
of pp32 family members are encoded by different genes: pp32 maps to
chromosome 15q22.3-q23, pp32r1 to chromosome 4 and pp32r2 to
chromosome 12.
The possibility that the switch from pp32 to pp32r1 and/or pp32r2 expression
is a causative event in prostate tumorigenesis raises the question of the
function of these clearly different but related proteins. The pp32 protein
may be a transcriptional regulator and pp32 expression levels seem to be associated
with cell proliferation4 but its exact function is not known.
The molecular switch that flips pp32 expression off and pp32r1/pp32r2 expression
on has not yet been elucidated. Also, it is not clear whether this switch
is a primary or secondary event because altered expression could be a downstream
effect of the aberrant function of other oncogenes or tumor suppressor proteins.
However, Kadkol et al.1 also show that unlike pp32
, pp32r1 and pp32r2 stimulate transformation of rat embryonic
fibroblasts when co-transfected with ras and myc. Perhaps manipulation
of the expression pattern of pp32 gene family members could delay tumorigenesis
or even induce reversal of the malignant phenotype. However, before planning
any therapeutic approaches based on these genes, more information is needed
about their precise role in tumor development.
In the 1940s, Huggins and Hodges5 showed that growth of prostate
cancer is androgen-dependent. Since then, induction of androgen withdrawal
by surgical or chemical castration has been the 'gold standard' treatment
for individuals with disseminated prostate carcinomas, and almost all patients
respond. However, if the patient lives long enough, the disease eventually
progresses despite androgen withdrawal therapy. Unfortunately, there is no
effective treatment for the androgen-independent prostate cancer that emerges.
Castration only abolishes testicular androgens, so anti-androgens are often
given in combination with castration (so-called maximal androgen blockade
therapy) to block the effects of androgens produced by the adrenal glands.
However, there is not much evidence that this combination is more effective
than castration alone.
Several hypotheses about the molecular mechanisms of tumor progression
during androgen withdrawal have been postulated. It is becoming clear that
androgen signal transduction pathways play an essential part in tumor progression
despite the existence of only very low levels of androgen. For example, serum
levels of prostate specific antigen (PSA)—the expression of which is
regulated by androgens—often increase as prostate carcinomas become
androgen-independent. Also, patients seem to benefit from the continuation
of androgen withdrawal even after the tumors become androgen-independent suggesting
that the androgen signaling pathway is still activated in these tumors.
One third of androgen-independent prostate carcinomas show amplification
and overexpression of the wild-type AR gene6 (see Fig.). Furthermore, AR mutations that alter the
function of this nuclear receptor in prostate cancer tissue have been characterized,
although the frequency of such mutations is still in dispute7.
The ARA70 co-activator alters the response of AR to anti-androgens in vitro,
suggesting that co-activators of AR may be involved in tumor progression8. The elegant study by Craft et al.2 demonstrates
that yet another AR mechanism could be involved in prostate cancer progression
during androgen withdrawal (see Fig.).
Using the LAPC-4 mouse xenograft model9, Craft and co-workers
showed that androgen-independent sublines of human prostate cancer xenografts
expressed higher levels of the HER-2/neu receptor tyrosine kinase than did
androgen-dependent sublines. Next, they overexpressed HER-2/neu in an LNCaP
prostate cancer cell line, which caused the cells to become androgen-independent.
Finally, overexpression of HER-2/neu increased the expression of PSA, especially
at low androgen levels, and activation of PSA transcription by HER-2/neu was
shown to require functional AR. This paper demonstrates the cross-talk between
the HER-2/neu tyrosine kinase and AR signal transduction pathways during prostate
cancer progression.
HER-2/neu is one of the best-studied genes involved in human malignancy.
Amplification and overexpression of HER-2/neu is found in 20−30 percent
of breast cancers. However, studies of HER-2/neu in prostate cancer remain
controversial7—some studies report overexpression of HER-2/neu,
others do not. To determine the importance of the Craft findings, more studies
are needed to determine the exact level of expression of HER-2/neu, particularly
in androgen-independent prostate cancer.
Possible mechanisms of androgen receptor (AR) involvement in the emergence
of androgen-independent prostate cancer. AR is a transcription factor that
is normally activated by its androgen ligand. During androgen withdrawal therapy,
the AR signal transduction pathway could by activated by amplification of
the AR gene (b), by AR gene mutations (c) or by
altered activity of AR co-activactors (d). In addition, the receptor
tyrosine kinase HER-2/neu might act directly (or indirectly through the ras/MAP
kinase signaling pathway) to activate the AR signal transduction pathway.
(a) Through these mechanisms, tumor cells could bypass growth inhibition
signals caused by androgen withdrawal, leading to the emergence of androgen-independent
prostate cancer.
If HER-2/neu is indeed involved in the emergence of androgen-independent
prostate cancer, we may see a new treatment modality sooner than we thought.
Recently, HerceptinTM, a monoclonal antibody against HER-2/neu, was approved
for the treatment of metastatic breast cancer10. HerceptinTM
is the first, and so far the only, example of a treatment modality directed
against a molecule apparently involved in the development of a solid tumor.
If Craft and co-workers are right, then HerceptinTM may also be useful
in treating androgen-independent prostate cancer.
Advanced prostate cancer may be (almost) androgen-independent but this
does not necessarily mean that the AR signaling pathway is not involved in
tumor progression. Understanding how AR is activated at low androgen levels
will be important for the development of new therapies to treat this otherwise
incurable disease.
Kadkol, S.S., Brody, J.R., Pevsner, J., Bai, J. & Pasternack, G.R. Modulation of oncogenic potential by alternative gene usage in human prostate cancer. Nature Med.5, 275−279 (1999). | Article | PubMed | ISI | ChemPort |
Craft, N., Shostak, Y., Carey M. & Sawyers, S.L. A mechanism for hormone independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nature Med.5, 280−285 (1999). | Article | PubMed | ISI | ChemPort |
Malek, S.N., Katumuluwa, A.I. & Pasternack, G.R. Identification and preliminary characterization of two related proliferation-associated nuclear phosphoproteins. J. Biol. Chem.265, 13400−13409 (1990). | PubMed | ISI | ChemPort |
Huggins, C. & Hodges C.V. The effect of castration, of estrogens and of androgen injection on serum phosphatase in metastatic carcinoma of prostate. Cancer Res.1, 293−297 (1941). | ChemPort |
Visakorpi, T. et al.In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet.9, 401−406 (1995). | Article | PubMed | ISI | ChemPort |
Kallioniemi, O.-P. & Visakorpi, T. Genetic basis and clonal evolution of human prostate cancer. Adv. Cancer Res.68, 225−255 (1996). | PubMed | ISI | ChemPort |
Miyamoto, H., Yeh, S., Wilding, G. & Chang, C. Promotion of agonist activity of anti-androgens by the androgen receptor co-activator, ARA70, in human prostate cancer DU145 cells. Proc. Natl. Acad. Sci. USA95, 7379−7384 (1998). | Article | PubMed | ChemPort |
Klein, K.A. et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nature Med.3, 402−408 (1997). | Article | PubMed | ISI | ChemPort |
