Oncology Abstracts

This study was conducted to define the role of Dachshund in prostate cancer, through assessing human prostate cancer samples and through genetic deletion in the mouse. Prostate cancer (PCa), the second leading cause of death in American men. A better molecular understanding of the disease is necessary in order to develop novel targeted therapies of metastatic PCa. Known genetic drivers to tumor initiation include PTEN and NKX3.1 deletions, rearrangements of the TMPRSS2 gene to the oncogenic ETS transcription factor, ERG, and genetic predisposing factors include DNA-repair gene mutations. DACH1, initially cloned as an inhibitor of Elipse in Drosophila, was found to be reduced in abundance in several malignancies including breast and prostate cancer.

Results: Interrogation of the genomic sequence of prostate cancer from >490 patients from 5 population cohort showed homozygous deletion of DACH1 in 18% (N=61), 11% (N=136), 10% (N=492), 7% (N=103) and 3% (N=150). DACH1 gene deep deletions was more prevalent in the metastasis than in the primary tumors. AR activity levels (AR score derived from expression of AR target genes) showed a significant increase of AR score in the DACH1 deletion group as compared to Normal (P=2×10⁻⁵ by t-test) and ERG1 mutation groups (P=0.003 by t-test). The Transgenic Adenocarcinoma Mouse Prostate (TRAMP) transgenic, Dach1^fl/fl, and Probasin-Cre, ROSA26^mT/mG transgenic mice were used to generate a prostate epithelial cell specific Dach1 gene knockout mouse (Probasin-Cre-Dach1^fl/fl ROSA26^mT/mG-TRAMP) lines. Prostate specific deletion of the murine Dach1 gene enhanced progression of prostatic intraepithelial neoplasia (PIN), associated with increased prostate epithelial cell proliferation, epithelial mesenchymal transition (EMT), DNA damage and inflammation. DACH1 bound and restrained the AR and was recruited to ARE in a casodex-dependent manner.

Conclusions: DACH1 gene deletion may define a distinct subclass of prostate cancer that may benefit from PARP inhibitors, and platinum-based chemotherapy.