AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer
Androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558613800127 |
| _version_ | 1819200246504226816 |
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| author | Gang Liu Cynthia Sprenger Shihua Sun Kathryn Soriano Epilepsia Kathleen Haugk Xiaotun Zhang Ilsa Coleman Peter S. Nelson Stephen Plymate |
| author_facet | Gang Liu Cynthia Sprenger Shihua Sun Kathryn Soriano Epilepsia Kathleen Haugk Xiaotun Zhang Ilsa Coleman Peter S. Nelson Stephen Plymate |
| author_sort | Gang Liu |
| collection | DOAJ |
| description | Androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed as one of the most important mechanisms underlying failure of therapy. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds more credence to this idea. Expression of AR-Vs in metastases portends a rapid progression of the tumor. However, the precise role of the AR-Vs in CRPC still remains unknown. ARv567es is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter-driven ARv567es transgenic mouse, Pb-ARv567es, to evaluate the role of ARv567es in both autonomous prostate growth and progression to CRPC. We found that expression of ARv567es in the prostate results in epithelial hyperplasia by 16 weeks and invasive adenocarcinoma is evident by 1 year of age. The underlying genetic cellular events involved a cell cycle-related transcriptome and differential expression of a spectrum of genes that are critical for tumor initiation and progression. These findings indicate that ARv567es could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-ARv567es mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined. |
| first_indexed | 2024-12-23T03:29:11Z |
| format | Article |
| id | doaj.art-ac1e20ccf5374f3582108d79ea40e1b9 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-23T03:29:11Z |
| publishDate | 2013-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-ac1e20ccf5374f3582108d79ea40e1b92022-12-21T18:01:46ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022013-09-011591009101710.1593/neo.13784AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate CancerGang Liu0Cynthia Sprenger1Shihua Sun2Kathryn Soriano Epilepsia3Kathleen Haugk4Xiaotun Zhang5Ilsa Coleman6Peter S. Nelson7Stephen Plymate8Department of Medicine, University of Washington, Seattle, WADepartment of Medicine, University of Washington, Seattle, WADepartment of Medicine, University of Washington, Seattle, WADepartment of Medicine, University of Washington, Seattle, WAVeteran Affairs Puget Sound Health Care System, Seattle, WAUrology Department, University of Washington, Seattle, WADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WADivision of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WADepartment of Medicine, University of Washington, Seattle, WAAndrogen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer but is uniformly marked by progression to castration-resistant prostate cancer (CRPC) after a period of regression. Continued activation of androgen receptor (AR) signaling is attributed as one of the most important mechanisms underlying failure of therapy. Recently, the discovery of constitutively active AR splice variants (AR-Vs) adds more credence to this idea. Expression of AR-Vs in metastases portends a rapid progression of the tumor. However, the precise role of the AR-Vs in CRPC still remains unknown. ARv567es is one of the two AR variants frequently found in human CRPC xenografts and metastases. Herein, we developed a probasin (Pb) promoter-driven ARv567es transgenic mouse, Pb-ARv567es, to evaluate the role of ARv567es in both autonomous prostate growth and progression to CRPC. We found that expression of ARv567es in the prostate results in epithelial hyperplasia by 16 weeks and invasive adenocarcinoma is evident by 1 year of age. The underlying genetic cellular events involved a cell cycle-related transcriptome and differential expression of a spectrum of genes that are critical for tumor initiation and progression. These findings indicate that ARv567es could induce tumorigenesis de novo and signifies the critical role of AR-Vs in CRPC. Thus, the Pb-ARv567es mouse could provide a novel model in which the role of AR variants in prostate cancer progression can be examined.http://www.sciencedirect.com/science/article/pii/S1476558613800127 |
| spellingShingle | Gang Liu Cynthia Sprenger Shihua Sun Kathryn Soriano Epilepsia Kathleen Haugk Xiaotun Zhang Ilsa Coleman Peter S. Nelson Stephen Plymate AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer Neoplasia: An International Journal for Oncology Research |
| title | AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer |
| title_full | AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer |
| title_fullStr | AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer |
| title_full_unstemmed | AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer |
| title_short | AR Variant ARv567es Induces Carcinogenesis in a Novel Transgenic Mouse Model of Prostate Cancer |
| title_sort | ar variant arv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558613800127 |
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