Abstract | BACKGROUND:
Androgens play a crucial role in prostate cancer, hence the androgenic pathway has become an important target of therapeutic intervention. Previously we discovered that gene fusions between the 5'-untranslated region of androgen regulated gene TMPRSS2 and the ETS transcription factor family members were present in a majority of the prostate cancer cases. The resulting aberrant overexpression of ETS genes drives tumor progression. METHODS: Here, we evaluated the expression levels of 5α-reductase isoenzymes in prostate cancer cell lines and tissues. We tested the effect of dutasteride, a 5α-reductase inhibitor, in TMPRSS2-ERG fusion-positive VCaP cell proliferation and cell invasion. We also evaluated the effect of dutasteride on the TMPRSS2-ERG fusion gene expression. Finally, we tested dutasteride alone or in combination with an anti- androgen in VCaP cell xenografts tumor model. RESULTS: CONCLUSIONS: Our findings suggest that dutasteride can inhibit ERG fusion-positive cell growth and in combination with anti- androgen, significantly reduce the tumor burden. Our study suggests that anti- androgens used in combination with dutasteride could synergistically augment the therapeutic efficacy in the treatment of ETS-positive prostate cancer.
|
Authors | Bushra Ateeq, Adaikkalam Vellaichamy, Scott A Tomlins, Rui Wang, Qi Cao, Robert J Lonigro, Kenneth J Pienta, Sooryanarayana Varambally |
Journal | The Prostate
(Prostate)
Vol. 72
Issue 14
Pg. 1542-9
(Oct 01 2012)
ISSN: 1097-0045 [Electronic] United States |
PMID | 22415461
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2012 Wiley Periodicals, Inc. |
Chemical References |
- 5-alpha Reductase Inhibitors
- Azasteroids
- Isoenzymes
- Oncogene Proteins, Fusion
- RNA, Neoplasm
- TMPRSS2-ETS fusion protein, human
- Dutasteride
|
Topics |
- 5-alpha Reductase Inhibitors
(pharmacology)
- Animals
- Azasteroids
(pharmacology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Dutasteride
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Isoenzymes
(pharmacology)
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasms, Hormone-Dependent
(drug therapy, enzymology, genetics, metabolism)
- Oncogene Proteins, Fusion
(antagonists & inhibitors, genetics, metabolism)
- Prostatic Neoplasms
(drug therapy, enzymology, genetics, metabolism)
- RNA, Neoplasm
(chemistry, genetics)
- Random Allocation
- Reverse Transcriptase Polymerase Chain Reaction
- Xenograft Model Antitumor Assays
|