ABSTRACT
Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5'-diphosphate (ADP)-ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated- and Rad3-related (ATR), and Chk1.
Subject(s)
DNA Damage , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Prostatic Neoplasms/drug therapy , Proto-Oncogene Proteins c-myb/antagonists & inhibitors , Thiophenes/pharmacology , Urea/analogs & derivatives , Animals , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Castration , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Male , Mice , Mice, Nude , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-myb/genetics , Proto-Oncogene Proteins c-myb/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Urea/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A 55-year-old male complained about urinary frequency, micturition pain, and right abdominal pain. Ultrasonography, computed tomography, and magnetic resonance imaging revealed severe vesicorectal fistula which was induced by either bladder carcinoma or rectal carcinoma. Total pelvic exenteration was performed. Histopathological examination revealed rectal adenocarcinoma with invasion of the urinary bladder. Twelve months after the surgery, the patient exhibited no sign nor symptom of local recurrence or metastatic disease.
ABSTRACT
We report a case of female urethral cancer. A 67-year-old female complained of a pain in the left buttocks. Magnetic resonance imaging (MRI) revealed a urethral tumor, which invaded the bladder wall and left buttocks tissue. Transurethral resection was performed. Histopathological examinations revealed squamous cell carcinoma of the urethra. The case was diagnosed as stage D4 urethral cancer according to the Grabstald's classification. Radiotherapies with a total dose of 57.5 Gy were performed on the primary and invaded sites. However, she died 6 months after the radiotherapy.
