Download DO TYPE I RECEPTOR TYROSINE KINASES DRIVE HORMONE

THE ROLE OF THE PI3K/AKT CASCADE IN HORMONE
REFRACTORY PROSTATE CANCER
J Edwards*, P Traynor, L Tam, A. F. Munro, J.M.S. Bartlett
[email protected]
Endocrine Cancer Group, Section of Surgical and Translational Sciences,
Division of Cancer Sciences and Molecular Pathology, University of Glasgow,
Glasgow, UK
INTRODUCTION. Prostate cancer is the second most common male
malignancy in the western world. Treatment of advanced prostate cancer relies
on androgen deprivation. Although the majority of patients initially respond to
androgen deprivation therapy, the mean time to relapse is 12-18 months.
Recently, major advances have been made in understanding post-translational
modifications to the androgen receptor (AR). Phosphorylation of AR, in vitro,
via the PI3K/Akt signal transduction pathways, has been shown to activate the
AR and sensitise it to low circulating levels of androgens (1). We recently
reported that genes for members of the PI3K/Akt pathway are more commonly
amplified in hormone refractory tumours compared to matched hormone sensitive
tumours (2). Here we tested the functional significance of these modifications in
the development of hormone refractory prostate cancer.
METHODS. AR protein expression, AR phosphorylation at the Akt consensus
site Serine 210 (phospho AR) and phosphorylated Akt (at both the Theronine
308 and Serine 473 phosphorylation sites) was determined by
immunohistochemistry in a cohort of matched tumour pairs (one taken before
and one after hormone relapse) from 53 prostate cancer patients. Detection and
visualisation was achieved using the LSAB+ kit (DAKO Cytomation) for AR
and phospho AR) or EnVision (DAKO Cytomation) (phospho Akt) and DAB kit
(Vector Laboratories). Two independent observers using a weighted histoscore
method scored each section.
RESULTS. AR expression levels were significantly higher in hormone
resistant tumours compared to matched hormone sensitive tumours from the
same patient, (130 (55-167) vs 94.5 (55-120) p=0.019), AR expression was not
associated with patient survival (3). Phospho AR expression was also
significantly higher in hormone resistant tumours compared to matched hormone
sensitive tumours (107.5(57.5-175.5) vs 50(0-92) p=0.0005). Further, patient
phospho AR expression above the median value in hormone refractory tumours
had significantly shorter survival from time of biochemical relapse than patients
with low (below the median) phospho AR expression (p=0.0076), this was also
observed for shorter overall survival (p=0.034).
Almost half the patients in this study showed a marked increase in phospho AR
expression with the development of hormone refractory disease (47%, 25/53).
In these patients a significant reduction in time to death from biochemical
relapse (p=0.0004) and overall survival (p=0.023) was observed relative to
patients who had a decrease in phospho AR expression (8%, 4/53) or no change
in phospho AR expression (45%, 24/53).
Protein expression of phospho AR was not linked with expression of HER2,
pHER2, EGFR, and pEGFR; up stream regulators of the PI3K cascade.
However membrane expression of Akt phosphorylated at serine 473, does
positively correlate with phospho AR expression (p=0.049).
CONCLUSION. Activation of AR by phosphorylation at the Akt consensus site
(Serine 210) is significantly increased with the development of hormone
refractory prostate cancer and high expression of phospho AR is associated with
significantly reduced patient survival. Akt activation is linked to AR activation
suggesting that inhibition of the PI3K/Akt cascade, to inhibit AR
phosphorylation could be a novel therapeutic target for treatment of hormone
refractory prostate cancer.
ACKNOWLEDGMENT. This work was supported by TENOVUS Scotland and
theProstate Cancer Charitable Trust.
REFERENCES
1. Ghosh P.M., Malik S., Bedolla R., Kreisberg J.I. (2003) Current Drug
Metabolism 4 487-496
2. Edwards J., Krishna N.S., Witton C..J, Bartlett J.M.S. (2003). Clin. Cancer
Res. 9, 5271-5281.
3. Edwards J., Krishna N.S., Bartlett J.M.S. (2003). Brit J. Cancer 198, 237-244