Abstract
Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial- mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5+/Ck8+ intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1529-1539 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 289 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jan 17 2014 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
- Medicine(all)
Cite this
Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. / Sun, Feng; Chen, He Ge; Li, Wei; Yang, Xi; Wang, Xin; Jiang, Richeng; Guo, Zhiyong; Chen, Hegang; Huang, Jiaoti; Borowsky, Alexander D; Qiu, Yun.
In: Journal of Biological Chemistry, Vol. 289, No. 3, 17.01.2014, p. 1529-1539.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors
AU - Sun, Feng
AU - Chen, He Ge
AU - Li, Wei
AU - Yang, Xi
AU - Wang, Xin
AU - Jiang, Richeng
AU - Guo, Zhiyong
AU - Chen, Hegang
AU - Huang, Jiaoti
AU - Borowsky, Alexander D
AU - Qiu, Yun
PY - 2014/1/17
Y1 - 2014/1/17
N2 - Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial- mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5+/Ck8+ intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.
AB - Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial- mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5+/Ck8+ intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.
UR - http://www.scopus.com/inward/record.url?scp=84892645101&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892645101&partnerID=8YFLogxK
U2 - 10.1074/jbc.M113.492140
DO - 10.1074/jbc.M113.492140
M3 - Article
C2 - 24297183
AN - SCOPUS:84892645101
VL - 289
SP - 1529
EP - 1539
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 3
ER -