Table 2.

Evidence for cohesin's involvement in cancer

CancerCohesin subunit involved (context of study)Description of studyReference
Breast cancerRAD21 mRNA expression (cell lines)Quantitative gene expression analysis revealed that RAD21 mRNA expression is lower in normal and immortalized breast cancer cell lines compared with 9/11 tumorigenic breast cancer lines.149
siRNA knockdown of RAD21 effectively inhibited proliferation of MCF-7 and T-47D cell lines.
RAD21 knockdown in MCF-7 cell line renders cells more sensitive to the DNA-damaging chemotherapeutic agents etoposide and bleomycin.
Breast cancerRAD21 mRNA expression (primary tumors)cDNA microarray analysis of primary breast tumors from patients without tumor cells in local lymph nodes at diagnosis (lymph node–negative) identified a gene expression signature strongly predictive of a short interval to distant metastases (poor-prognosis signature). RAD21 was found to be significantly upregulated in the poor-prognosis signature.95
Breast cancerRAD21 mRNA expression (primary tumors)cDNA microarrays were profiled to identify functional pathways that determine the outcome of breast cancer patients with supraclavicular lymph node metastases.96
Thirty-one breast cancer patients with supraclavicular lymph node metastasis without distant metastases were divided into poor, intermediate, or good-prognosis groups.
Wnt signaling and mitochondrial apoptosis pathways emerged, with 6 genes (DVL1, VDAC2, BIRC5, Stathmin1, PARP1, and RAD21) found to be overexpressed in the poor-prognosis group compared with the good-prognosis group.
Breast cancerRAD21 mRNA expression in response to BRCA1 overexpression (cell lines)Suppression subtractive hybridization was used to compare the expression profiles of control MCF7 cells with MCF7 cells ectopically expressing BRCA1, to identify genes whose expression is regulated by BRCA1.153
RAD21 is upregulated following overexpression of BRCA1.
Breast cancerRAD21 protein and mRNA expression and RAD21 gene amplification (primary tumors)Immunohistochemistry was used to evaluate RAD21 expression in a cohort of in situ and invasive breast cancers.97
RAD21 levels were significantly lower in invasive cancers compared with in situ cancers. Levels of RAD21 correlated with larger tumor size and lymph node involvement but not with tumor grade, HER2 status, or ER status. Positive RAD21 protein expression was seen in 37% luminal, 24% basal, 22% HER2, and 18% null cancers, and significantly correlated with shorter relapse-free survival. RAD21 expression correlated with relapse in grade 3 but not in grade 1 or 2 tumors. Further analysis of grade 3 tumors according to subtype showed a significant correlation between RAD21 expression and shorter relapse-free survival in the luminal, basal, and HER2 cancers but not the null-type cancers.
In patients not treated with chemotherapy, there was no correlation between RAD21 expression and overall survival, whereas in patients treated with chemotherapy, there was a significantly shorter overall survival in patients whose tumors were RAD21-positive.
Array comparative genomic hybridization and transcription data from 48 grade 3 invasive ductal carcinomas of luminal, basal-like, and HER2 subtypes were integrated to examine the association of RAD21 mRNA expression with RAD21 copy number.
RAD21 mRNA expression correlated with gene copy number in luminal, basal, and HER2 tumors, suggesting that the positive RAD21 expression observed in a subset of grade 3 tumors may be due to gene amplification.
shRNA-mediated gene silencing of RAD21 in the MDA-MB-231 basal-like breast cancer cell line rendered the cells more sensitive to the chemotherapy drugs cyclophosphamide and 5-fluorouracil in a manner that directly correlated with the level of RAD21 expression.
Prostate cancerRAD21 mRNA expression and RAD21 gene amplification (cell lines and primary tumors)Sought to identify genes that are overexpressed, especially from gene amplification, in prostate cancer.154
Quantitative RT-PCR revealed that RAD21 expression was increased in the PC-3 prostate cancer cell line. In tumors, RAD21 was 1 of 7 genes that were overexpressed, mainly in samples found to contain amplification in the chromosomal regions harboring the genes. Expression of these 7 genes was examined by quantitative RT-PCR in cases of benign prostate hyperplasia, untreated prostate carcinoma, and hormone-refractory prostate carcinoma. RAD21 expression was significantly higher in carcinomas than in benign prostate hyperplasia.
FISH results showed that RAD21 was amplified in PC-3 cells. Furthermore, in a screen of 10 xenografts and 12 hormone-refractory prostate carcinomas, RAD21 showed high-level amplification in 32% of samples.
Oral squamous cell carcinomaRAD21 expression in invasive growth pattern vs expansive growth pattern (primary tumors)Investigated the relevance of RAD21 in invasion and metastases of squamous cell carcinoma.98
Laser microdissection and quantitative PCR revealed that RAD21 expression was significantly decreased in areas of INF-γ invasion (associated with poorer prognosis) compared with areas that showed INF-α invasion.
Colorectal cancerMutations in several subunits (primary tumors)Systematically identified somatic mutations in potential CIN genes in colorectal cancers by determining the sequence of 102 human homologs of 96 yeast CIN genes known to function in various aspects of chromosome transmission fidelity.53
In a panel of 132 colorectal cancers, 11 somatic mutations, distributed among 5 genes, were identified. Ten of these mutations were found in the genes encoding the cohesin subunits SMC1L1, NIPBL, CSPG6, and STAG3.
RNAi was used to reduce SMC1L1 and CSPG6 protein levels, and resulted in CIN and chromatid cohesion defects in human cells.
Colon carcinomaSMC3 mRNA (cell lines and primary tumors)SMC3 expression was increased in mouse colorectal carcinoma cells compared with a primary colon cell line. Similarly, SMC3 expression was increased in colon carcinoma tissue compared with normal colon tissue, and 5 independent human colon carcinoma cell lines displayed the same degree of SMC3 overexpression as the colon carcinoma sample.155
70% of human colon carcinoma tissue samples (n = 19) displayed a significant increase in SMC3 mRNA levels compared with matched normal colon tissue samples.
Myeloid leukemiaRAD21 and STAG2 gene deletions (leukemia cells)To identify potential new genes involved in myeloid diseases, array comparative genomic hybridization was performed on 167 samples, including myelodysplastic syndrome, chronic myelomonocytic leukemia, and acute myeloid leukemia.156
In a case of chronic myelomonocytic leukemia diagnosed in 2007, a small heterozygous deletion at 8q24 was revealed. This region includes the RAD21 gene. This chronic myelomonocytic leukemia transformed to M5 FAB acute myeloid leukemia in 2008, and array comparative genomic hybridization again revealed the RAD21 loss but no other additional alteration. The patient died 6 months after transformation.
In a case of M6 FAB acute myeloid leukemia diagnosed in 2005, a small deletion centered on the STAG2 gene was identified. The patient died in 2007, 5 months after relapse.
In both cases, the karyotype did not show any abnormality, and no other array comparative genomic hybridization alterations were noticed.