Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells
An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR e...
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Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 1997-04, Vol.11 (4), p.450-459 |
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creator | Tan, Jiann-an Sharief, Yousuf Hamil, Katherine G Gregory, Christopher W Zang, De-Ying Sar, Madhabananda Gumerlock, Paul H deVere White, Ralph W Pretlow, Thomas G Harris, Stephen E Wilson, Elizabeth M Mohler, James L French, Frank S |
description | An androgen receptor (AR) gene mutation
identified in the androgen-dependent human prostate cancer xenograft,
CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT
for histidine to TAT for tyrosine and abolished a restriction site for
the endonuclease SfaNI. SfaNI digestion of AR exon H DNA
from normal but not from prostate cancer tissue indicated H874Y is a
somatic mutation that occurred before the initial tumor transplant.
CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in
size to the AR mRNA in human benign prostatic hyperplasia. AR protein
is present in cell nuclei by immunostaining as in other
androgen-responsive tissues. Transcriptional activity of recombinant
H874Y transiently expressed in CV1 cells in the presence of
testosterone or dihydrotestosterone was similar to that of wild type
AR. With dihydrotestosterone at a near physiological concentration
(0.01 nm), H874Y and wild type AR induced
2-fold greater luciferase activity than did the LNCaP mutant AR
T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100
nm) with H874Y stimulated a 3- to 8-fold
greater response than with wild type AR and at 100
nm the response was similar with the LNCaP
mutant. H874Y, like the LNCaP cell mutant, was more responsive to
estradiol and progesterone than was wild type AR. The antiandrogen
hydroxyflutamide (10 nm) had greater agonist
activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR
mutations that alter ligand specificity may influence tumor progression
subsequent to androgen withdrawal by making the AR more responsive to
adrenal androgens or antiandrogens. |
doi_str_mv | 10.1210/mend.11.4.9906 |
format | Article |
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identified in the androgen-dependent human prostate cancer xenograft,
CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT
for histidine to TAT for tyrosine and abolished a restriction site for
the endonuclease SfaNI. SfaNI digestion of AR exon H DNA
from normal but not from prostate cancer tissue indicated H874Y is a
somatic mutation that occurred before the initial tumor transplant.
CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in
size to the AR mRNA in human benign prostatic hyperplasia. AR protein
is present in cell nuclei by immunostaining as in other
androgen-responsive tissues. Transcriptional activity of recombinant
H874Y transiently expressed in CV1 cells in the presence of
testosterone or dihydrotestosterone was similar to that of wild type
AR. With dihydrotestosterone at a near physiological concentration
(0.01 nm), H874Y and wild type AR induced
2-fold greater luciferase activity than did the LNCaP mutant AR
T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100
nm) with H874Y stimulated a 3- to 8-fold
greater response than with wild type AR and at 100
nm the response was similar with the LNCaP
mutant. H874Y, like the LNCaP cell mutant, was more responsive to
estradiol and progesterone than was wild type AR. The antiandrogen
hydroxyflutamide (10 nm) had greater agonist
activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR
mutations that alter ligand specificity may influence tumor progression
subsequent to androgen withdrawal by making the AR more responsive to
adrenal androgens or antiandrogens.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/mend.11.4.9906</identifier><identifier>PMID: 9092797</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Androgen Antagonists - pharmacology ; Animals ; Chromosome Mapping ; Dehydroepiandrosterone - pharmacology ; Epithelium - metabolism ; Estradiol - pharmacology ; Flutamide - analogs & derivatives ; Flutamide - pharmacology ; Haplorhini ; Humans ; Ligands ; Male ; Mutation ; Progesterone - pharmacology ; Prostatic Neoplasms - metabolism ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Transcription, Genetic ; Transcriptional Activation ; Transfection ; Transplantation, Heterologous ; Tumor Cells, Cultured</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 1997-04, Vol.11 (4), p.450-459</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3226-62fe7a59b66fffab8dccece2ad73d9317fe53e740c3b6a21e622e56135a8fbab3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9092797$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tan, Jiann-an</creatorcontrib><creatorcontrib>Sharief, Yousuf</creatorcontrib><creatorcontrib>Hamil, Katherine G</creatorcontrib><creatorcontrib>Gregory, Christopher W</creatorcontrib><creatorcontrib>Zang, De-Ying</creatorcontrib><creatorcontrib>Sar, Madhabananda</creatorcontrib><creatorcontrib>Gumerlock, Paul H</creatorcontrib><creatorcontrib>deVere White, Ralph W</creatorcontrib><creatorcontrib>Pretlow, Thomas G</creatorcontrib><creatorcontrib>Harris, Stephen E</creatorcontrib><creatorcontrib>Wilson, Elizabeth M</creatorcontrib><creatorcontrib>Mohler, James L</creatorcontrib><creatorcontrib>French, Frank S</creatorcontrib><title>Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>An androgen receptor (AR) gene mutation
identified in the androgen-dependent human prostate cancer xenograft,
CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT
for histidine to TAT for tyrosine and abolished a restriction site for
the endonuclease SfaNI. SfaNI digestion of AR exon H DNA
from normal but not from prostate cancer tissue indicated H874Y is a
somatic mutation that occurred before the initial tumor transplant.
CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in
size to the AR mRNA in human benign prostatic hyperplasia. AR protein
is present in cell nuclei by immunostaining as in other
androgen-responsive tissues. Transcriptional activity of recombinant
H874Y transiently expressed in CV1 cells in the presence of
testosterone or dihydrotestosterone was similar to that of wild type
AR. With dihydrotestosterone at a near physiological concentration
(0.01 nm), H874Y and wild type AR induced
2-fold greater luciferase activity than did the LNCaP mutant AR
T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100
nm) with H874Y stimulated a 3- to 8-fold
greater response than with wild type AR and at 100
nm the response was similar with the LNCaP
mutant. H874Y, like the LNCaP cell mutant, was more responsive to
estradiol and progesterone than was wild type AR. The antiandrogen
hydroxyflutamide (10 nm) had greater agonist
activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR
mutations that alter ligand specificity may influence tumor progression
subsequent to androgen withdrawal by making the AR more responsive to
adrenal androgens or antiandrogens.</description><subject>Androgen Antagonists - pharmacology</subject><subject>Animals</subject><subject>Chromosome Mapping</subject><subject>Dehydroepiandrosterone - pharmacology</subject><subject>Epithelium - metabolism</subject><subject>Estradiol - pharmacology</subject><subject>Flutamide - analogs & derivatives</subject><subject>Flutamide - pharmacology</subject><subject>Haplorhini</subject><subject>Humans</subject><subject>Ligands</subject><subject>Male</subject><subject>Mutation</subject><subject>Progesterone - pharmacology</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Transcription, Genetic</subject><subject>Transcriptional Activation</subject><subject>Transfection</subject><subject>Transplantation, Heterologous</subject><subject>Tumor Cells, Cultured</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v1DAQtRCoLIUrNySfuCX1OIljH1dpS5EWqCoQ3CzHmbSpNk6wHUT_Bz8Yp7vqDXGaw_uYN_MIeQssBw7sbETX5QB5mSvFxDOyAVWWmVJQPycbJqXMpGTqJXkVwj1jUFYSTsiJYorXqt6QP-d499D5CefBuDRDRD85pFsbh18mYqCflmhcpNsVvUVHb9DiHCcf6MXv2WMI2NHB0XiHT5zsHOcUC5PsahmNo9ercXKjjXEWPf2Bbrr1po-0-X7DOU2r6e5zY65pg_t9eE1e9GYf8M1xnpJvlxdfm6ts9-XDx2a7y2zBucgE77E2lWqF6PvetLKzNoXjpquLThVQ91gVWJfMFq0wHFBwjpWAojKyb01bnJL3B9_ZTz8XDFGPQ7ApgXE4LUHXUgHIqvwvEQSvQEiRiPmBaNPFwWOvZz-Mxj9oYHrtS699aQBd6rWvJHh3dF7aEbsn-rGghFcHPMkm6weHjz_X99PiXfrNv3z_AtXeppk</recordid><startdate>199704</startdate><enddate>199704</enddate><creator>Tan, Jiann-an</creator><creator>Sharief, Yousuf</creator><creator>Hamil, Katherine G</creator><creator>Gregory, Christopher W</creator><creator>Zang, De-Ying</creator><creator>Sar, Madhabananda</creator><creator>Gumerlock, Paul H</creator><creator>deVere White, Ralph W</creator><creator>Pretlow, Thomas G</creator><creator>Harris, Stephen E</creator><creator>Wilson, Elizabeth M</creator><creator>Mohler, James L</creator><creator>French, Frank S</creator><general>Endocrine Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7X8</scope></search><sort><creationdate>199704</creationdate><title>Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells</title><author>Tan, Jiann-an ; Sharief, Yousuf ; Hamil, Katherine G ; Gregory, Christopher W ; Zang, De-Ying ; Sar, Madhabananda ; Gumerlock, Paul H ; deVere White, Ralph W ; Pretlow, Thomas G ; Harris, Stephen E ; Wilson, Elizabeth M ; Mohler, James L ; French, Frank S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3226-62fe7a59b66fffab8dccece2ad73d9317fe53e740c3b6a21e622e56135a8fbab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Androgen Antagonists - pharmacology</topic><topic>Animals</topic><topic>Chromosome Mapping</topic><topic>Dehydroepiandrosterone - pharmacology</topic><topic>Epithelium - metabolism</topic><topic>Estradiol - pharmacology</topic><topic>Flutamide - analogs & derivatives</topic><topic>Flutamide - pharmacology</topic><topic>Haplorhini</topic><topic>Humans</topic><topic>Ligands</topic><topic>Male</topic><topic>Mutation</topic><topic>Progesterone - pharmacology</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Receptors, Androgen - genetics</topic><topic>Receptors, Androgen - metabolism</topic><topic>Transcription, Genetic</topic><topic>Transcriptional Activation</topic><topic>Transfection</topic><topic>Transplantation, Heterologous</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tan, Jiann-an</creatorcontrib><creatorcontrib>Sharief, Yousuf</creatorcontrib><creatorcontrib>Hamil, Katherine G</creatorcontrib><creatorcontrib>Gregory, Christopher W</creatorcontrib><creatorcontrib>Zang, De-Ying</creatorcontrib><creatorcontrib>Sar, Madhabananda</creatorcontrib><creatorcontrib>Gumerlock, Paul H</creatorcontrib><creatorcontrib>deVere White, Ralph W</creatorcontrib><creatorcontrib>Pretlow, Thomas G</creatorcontrib><creatorcontrib>Harris, Stephen E</creatorcontrib><creatorcontrib>Wilson, Elizabeth M</creatorcontrib><creatorcontrib>Mohler, James L</creatorcontrib><creatorcontrib>French, Frank S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tan, Jiann-an</au><au>Sharief, Yousuf</au><au>Hamil, Katherine G</au><au>Gregory, Christopher W</au><au>Zang, De-Ying</au><au>Sar, Madhabananda</au><au>Gumerlock, Paul H</au><au>deVere White, Ralph W</au><au>Pretlow, Thomas G</au><au>Harris, Stephen E</au><au>Wilson, Elizabeth M</au><au>Mohler, James L</au><au>French, Frank S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>1997-04</date><risdate>1997</risdate><volume>11</volume><issue>4</issue><spage>450</spage><epage>459</epage><pages>450-459</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>An androgen receptor (AR) gene mutation
identified in the androgen-dependent human prostate cancer xenograft,
CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT
for histidine to TAT for tyrosine and abolished a restriction site for
the endonuclease SfaNI. SfaNI digestion of AR exon H DNA
from normal but not from prostate cancer tissue indicated H874Y is a
somatic mutation that occurred before the initial tumor transplant.
CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in
size to the AR mRNA in human benign prostatic hyperplasia. AR protein
is present in cell nuclei by immunostaining as in other
androgen-responsive tissues. Transcriptional activity of recombinant
H874Y transiently expressed in CV1 cells in the presence of
testosterone or dihydrotestosterone was similar to that of wild type
AR. With dihydrotestosterone at a near physiological concentration
(0.01 nm), H874Y and wild type AR induced
2-fold greater luciferase activity than did the LNCaP mutant AR
T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100
nm) with H874Y stimulated a 3- to 8-fold
greater response than with wild type AR and at 100
nm the response was similar with the LNCaP
mutant. H874Y, like the LNCaP cell mutant, was more responsive to
estradiol and progesterone than was wild type AR. The antiandrogen
hydroxyflutamide (10 nm) had greater agonist
activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR
mutations that alter ligand specificity may influence tumor progression
subsequent to androgen withdrawal by making the AR more responsive to
adrenal androgens or antiandrogens.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>9092797</pmid><doi>10.1210/mend.11.4.9906</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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ispartof | Molecular endocrinology (Baltimore, Md.), 1997-04, Vol.11 (4), p.450-459 |
issn | 0888-8809 1944-9917 |
language | eng |
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source | MEDLINE; Oxford Journals (Firm); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
subjects | Androgen Antagonists - pharmacology Animals Chromosome Mapping Dehydroepiandrosterone - pharmacology Epithelium - metabolism Estradiol - pharmacology Flutamide - analogs & derivatives Flutamide - pharmacology Haplorhini Humans Ligands Male Mutation Progesterone - pharmacology Prostatic Neoplasms - metabolism Receptors, Androgen - genetics Receptors, Androgen - metabolism Transcription, Genetic Transcriptional Activation Transfection Transplantation, Heterologous Tumor Cells, Cultured |
title | Dehydroepiandrosterone Activates Mutant Androgen Receptors Expressed in the Androgen-Dependent Human Prostate Cancer Xenograft CWR22 and LNCaP Cells |
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