5888

RAD51

RAD51 recombinase;RAD51;RAD51 recombinase

BRCA1/BRCA2-containing complex, subunit 5|DNA repair protein RAD51 homolog 1|RAD51 homolog A|RecA, E. coli, homolog of|RecA-like protein|recombination protein A

15q15.1

protein-coding

In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months.

BACKGROUND: Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. METHODS: expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). RESULTS: Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. CONCLUSIONS: BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain.

OBJECTIVE: To investigate the expression and clinical significance of RAD51 in laryngocarcinoma. METHOD: The expression of RAD51 in laryngocarcinoma and polyp of vocal cord tissues were determined by immunohistochemical staining. The results were analyzed and compared with the clinical stage, lymph node metastasis and pathologic grade. RESULT: (1) The expression of RAD51 in laryngocarcinoma group was extremely stronger than that in polyp of vocal cord group (P < 0.01). (2) There was significant difference for RAD51 expression in cancer cells between earlier clinical stage group and advanced clinical stage group (P < 0.01). (3) There was significant difference for RAD51 expression in different pathologic grades (P < 0.05). (4) There was also significant difference for RAD51 expression between groups with and without lymph node metastasis. CONCLUSION: RAD51 may play a critical role in tumorigenesis of laryngocarcinoma. RAD51 may be a potential marker for clinical diagnosis and treatment of Laryngocarcinoma. It may be significant in predicting clinical stage, pathologic grade and metastasis.

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) is beneficial in the setting of a complete pathological response. Rad51 expression affects both chemo- and radiosensitivity in many cancers; however, its role in ESCC is unclear. METHODS: Rad51 expression was investigated by immunohistochemical staining with resected specimens in 89 ESCC patients who underwent surgery without preoperative therapy. The association with Rad51 and clinicopathological factors was assessed. The expression of Rad51 was also investigated in pretreatment biopsy specimens in 39 ESCC patients who underwent surgery after NACRT and compared with the pathological response to NACRT. RESULTS: Lymph node metastasis was more frequently observed in Rad51-positive cases than negative cases (58.5 vs. 30.6%, P = 0.0168) in patients treated with surgery alone. Disease-specific survival was decreased in Rad51-positive cases compared to Rad51-negative cases (5 year survival: 79.6 vs. 59.3%, P = 0.0324). In NACRT patients, completed pathological responses were more frequently observed in Rad51-negative cases than in Rad51-positive cases (68.8 vs. 46.5%, P = 0.0171). CONCLUSIONS: Rad51 expression in ESCC was associated with lymph node metastasis and poor survival. Additionally, Rad51 expression in pretreatment biopsy specimens was a predictive factor for the response to NACRT.