Overexpression of RAD51 occurs in aggressive prostatic cancer

Abstract

Aims: To test the hypothesis that, in a matched series of prostatic cancers, either with or without BRCA1 or BRCA2 mutations, RAD51 protein expression is enhanced in association with BRCA mutation genotypes. Methods and results: RAD51 expression identified immunohistochemically was compared between prostatic cancers occurring in BRCA1 or BRCA2 mutation carriers and controls. RAD51 protein expression in the cytoplasm and nuclei of the benign tissues was significantly less than in the malignant tissues (P < 0.001). In all cancers, cytoplasmic expression of RAD51 was more prevalent and associated with higher Gleason score (P < 0.05) irrespective of BRCA mutational status, than its expression in benign tissues (P < 0.001). Although nuclear immunoreactivity was not observed in BRCA-associated cancers with Gleason score £7, it was significantly increased in all other groups of prostatic cancers when compared with benign tissues (P < 0.001). Conclusions: RAD51 protein is strongly expressed in high-grade prostatic cancers, whether sporadic or associated with BRCA germ-line mutations. Distinct localization of RAD51 between cytoplasm and nucleus, particularly in cancers of Gleason score £7, reflects distinct levels of RAD51 regulatory activity, from transcription to DNA repair. This biomarker may be of value in identifying patients requiring urgent treatment at diagnosis as well as in analysing biological mechanisms underlying aggressive phenotype of human prostatic cancer.

Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP

“…RAD51 has been reported to be overexpressed in high-grade prostate cancer (Gleason score >7), both in sporadic and those with germline BRCA mutations (44). Overexpression of RAD51 is seen in many forms of human cancers (45) and is clinically correlated with a more aggressive phenotype and decreased patient survival (44,46,47). Tumors with increased levels of RAD51 typically have higher HR activity which likely contributes to drug resistance.…”

“…In addition, downregulation of RAD51 by imatinib, a receptor tyrosine kinase inhibitor, sensitized PC-3 cells to ionizing radiation, mitomycin C, and gemcitabine (43). RAD51 has been reported to be overexpressed in high-grade prostate cancer (Gleason score >7), both in sporadic and those with germline BRCA mutations (44). Overexpression of RAD51 is seen in many forms of human cancers (45) and is clinically correlated with a more aggressive phenotype and decreased patient survival (44,46,47).…”

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

“…Depending on the availability of the building blocks, the cinnamide analogues (B) were also constructed by Heck coupling of the corresponding aromatic bromide with acrylamide C. After introducing motif 1 as an amine through amide coupling (D to E), the intermediates were cyclized under mild dehydration conditions with iodine and hexamethyldisilazine 18 to give the desired quinazolinone products (F). In this way, one series of compounds incorporated alkyl and cycloalkyl substituents (1)(2)(3)(4)(5)(6)(7)(8), and another series contained substituted aromatics with a variable spacer -(CH 2 )n-(n =0-2, 9-27). The latter series was designed to optimally target residues F195 and Y191 through piinteractions.…”

“…Upregulation of RAD51 is reported in several cancers, including triplenegative breast cancer (TNBC) 2 , glioblastoma 3 , prostate cancer 4 , and is a mechanism by which these tumors acquire resistance to therapies. HR-defective cells are significantly more sensitive to ionizing irradiation and DNA damaging chemotherapeutics 1 .…”

PARP inhibitors and stratified treatment of prostate cancer

“…BRCA mutations appear to be a poor prognostic factor associated with more advanced disease at presentation [9]. Nuclear expression of RAD51 is increased in prostate cancers with Gleason score >7 compared with ≤7 [10]. The DNA repair pathways are complex and involve multiple genes.…”