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and the Androgen Receptor in Normal Human Prostate Glands, Dysplasia, and in Primary and Metastatic Carcinoma
From the Department of Pathology,*
Schools of Medicine
and Veterinary Medicine, Tufts University, Boston, Massachusetts; the
Department of Surgery,
Division of Urology,
and the Department of Oncology,
University of
Massachusetts Medical School, Worcester, Massachusetts; the Department
of Urology,
Stanford University Medical
Center, Stanford, California; and Biogenex
Laboratories,¶
Mountain View, California
An antibody, GC-17, thoroughly characterized for
its specificity for estrogen receptor-ß (ER-ß), was used to
immunolocalize the receptor in histologically normal prostate,
prostatic intraepithelial neoplasia, primary
carcinomas, and in metastases to lymph nodes and bone.
Comparisons were made between ER-ß, estrogen receptor-
(ER-), and androgen receptor (AR) immunostaining in these
tissues. Concurrently, transcript expression of the three
steroid hormone receptors was studied by reverse
transcriptase-polymerase chain reaction analysis on laser
capture-microdissected samples of normal prostatic acini,
dysplasias, and carcinomas. In Western blot analyses,
GC-17 selectively identified a 63-kd protein expressed in normal and
malignant prostatic epithelial cells as well as in normal testicular
and prostatic tissues. This protein likely represents a
posttranslationally modified form of the long-form ER-ß,
which has a predicted size of 59 kd based on polypeptide length. In
normal prostate, ER-ß immunostaining was predominately
localized in the nuclei of basal cells and to a lesser extent stromal
cells. ER- staining was only present in stromal cell nuclei. AR
immunostaining was variable in basal cells but strongly expressed in
nuclei of secretory and stromal cells. Overall, prostatic
carcinogenesis was characterized by a loss of ER-ß expression at the
protein and transcript levels in high-grade dysplasias, its
reappearance in grade 3 cancers, and its diminution/absence in
grade 4/5 neoplasms. In contrast, AR was strongly expressed in
all grades of dysplasia and carcinoma. Because ER-ß is thought to
function as an inhibitor of prostatic growth, androgen
action, presumably mediated by functional AR and unopposed by
the ß receptor, may have provided a strong stimulus for
aberrant cell growth. With the exception of a small subset of
dysplasias in the central zone and a few carcinomas,
ER--stained cells were not found in these lesions. The majority of
bone and lymph node metastases contained cells that were immunostained
for ER-ß. Expression of ER-ß in metastases may have been influenced
by the local microenvironment in these tissues. In contrast,
ER--stained cells were absent in bone metastases and rare in lymph
nodes metastases. Irrespective of the site, AR-positive cells
were found in all metastases. Based on our recent finding of
anti-estrogen/ER-ß-mediated growth inhibition of prostate cancer
cells in vitro, the presence of ER-ß in
metastatic cells may have important implications for the treatment of
late-stage disease.
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