Abstract
Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor a (RXRα) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXRα function. There was also a significant change in the profile of secretory proteins in the RXRα mutant prostate relative to littermate controls with intact RXRα allele. Histopathologically, homozygous RXRα-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at ∼10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10-15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXRα, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4812-4819 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 62 |
| Issue number | 16 |
| State | Published - Aug 15 2002 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor α allele in the prostate epithelium. / Huang, Jiapeng; Powell, William C.; Khodavirdi, Ani C.; Wu, Jian; Makita, Takako; Cardiff, Robert; Cohen, Michael B.; Sucov, Henry M.; Roy-Burman, Pradip.
In: Cancer Research, Vol. 62, No. 16, 15.08.2002, p. 4812-4819.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor α allele in the prostate epithelium
AU - Huang, Jiapeng
AU - Powell, William C.
AU - Khodavirdi, Ani C.
AU - Wu, Jian
AU - Makita, Takako
AU - Cardiff, Robert
AU - Cohen, Michael B.
AU - Sucov, Henry M.
AU - Roy-Burman, Pradip
PY - 2002/8/15
Y1 - 2002/8/15
N2 - Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor a (RXRα) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXRα function. There was also a significant change in the profile of secretory proteins in the RXRα mutant prostate relative to littermate controls with intact RXRα allele. Histopathologically, homozygous RXRα-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at ∼10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10-15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXRα, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.
AB - Retinoids, which are important regulators of cell growth, differentiation, and apoptosis, have been used in treatment or chemoprevention of multiple cancers including prostate cancer. To elucidate the mechanism of action of retinoids in the context of the prostate, we used the Cre-loxP system to disrupt the retinoid X receptor a (RXRα) gene specifically in the prostatic epithelium of the mouse. Evidence for tissue-specific gene inactivation was obtained at DNA, RNA, and protein levels. Phenotypic changes in the prostate in the homozygous animals of different age groups ranging from 1 to 15 months were investigated. Developmentally, prostatic ductal branching appeared to be increased from the loss of RXRα function. There was also a significant change in the profile of secretory proteins in the RXRα mutant prostate relative to littermate controls with intact RXRα allele. Histopathologically, homozygous RXRα-deficient prostates showed multifocal hyperplasia as early as 4 months of age. Lesions, which could be described as low-grade prostatic intraepithelial neoplasias, were detected after 5 months. Subsequently, beginning at ∼10 months, high-grade prostatic intraepithelial neoplasias developed in some animals. The incidences of low-grade prostatic intraepithelial neoplasias and high-grade prostatic intraepithelial neoplasias among the animals 10-15 months of age were 62 and 17%, respectively. The heterozygous mutant mice also developed similar prostatic phenotypes but in a delayed manner, implying a role of haploinsufficiency. Together, these results indicated for the first time that a major component of retinoid action in the prostate is mediated by a retinoid receptor, RXRα, the inactivation of which in the prostatic epithelium leads to the development of preneoplastic lesions.
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UR - http://www.scopus.com/inward/citedby.url?scp=0037102446&partnerID=8YFLogxK
M3 - Article
C2 - 12183441
AN - SCOPUS:0037102446
VL - 62
SP - 4812
EP - 4819
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 16
ER -