Abstract
Breast cancer (BC) is the most common malignancy and the leading cause of death in women worldwide. Only 5%‐10% of mutations in BRCA genes are associated with familial breast tumours in Eastern countries, suggesting the contribution of other genes. Using a microarray gene expression profiling study of BC, we have recently identified BRIP1 (fivefold up‐regulation) as a potential gene associated with BC progression in the Omani population. Although BRIP1 regulates DNA repair and cell proliferation, the precise role of BRIP1 in BC cell invasion/metastasis has not been explored yet; this prompted us to test the hypothesis that BRIP1 promotes BC cell proliferation and invasion. Using a combination of cellular and molecular approaches, our results revealed differential overexpression of BRIP1 in different BC cell lines. Functional assays validated further the physiological relevance of BRIP1 in tumour malignancy, and siRNA‐mediated BRIP1 knockdown significantly reduced BC cell motility by targeting key motility‐associated genes. Moreover, down‐regulation of BRIP1 expression significantly attenuated cell proliferation via cell cycle arrest. Our study is the first to show the novel function of BRIP1 in promoting BC cell invasion by regulating expression of various downstream target genes. Furthermore, these findings provide us with a unique opportunity to identify BRIP1‐induced pro‐invasive genes that could serve as biomarkers and/or targets to guide the design of appropriate BC targeted therapies.
Highlights
Breast cancer (BC), a worldwide health problem, is the most common cancer in women, including the State of Qatar.[1]
BRIP1 interacts with BRCA1 to regulate cell cycle and DNA repair mechanisms, the role of BRIP1 in mediating tumour growth and progression has not been examined yet
We tested the hypothesis that BRIP1 can promote both BC cell growth and metastasis
Summary
Breast cancer (BC), a worldwide health problem, is the most common cancer in women, including the State of Qatar.[1]. BRIP1 plays major role in DNA repair, type J Fanconi anemia, development of various cancers, including BC.[8] BRIP1, a DNAdependent ATPase and a 5'-3' helicase that belongs to the DNAdependent RecQ DEAH helicase family, interacts with BRCA1 and is involved in double-stranded DNA breaks (DSB) repair during the G2-M phase of the cell cycle as well as in tumour suppression.[9,10] BRIP1 is expressed in both normal and malignant cells, and controls genome integrity via regulation of replication and homologous recombination,[11] DNA damage responses and checkpoints, which are crucial for genomic stability.[9] While BRCA1 and BRIP1 work as tumour suppressor genes,[10] when BRIP1 fails to bind BRCA1 in certain conditions, cells become sensitive to different genotoxic stresses with aberrant homologous DNA repair function.[12] Identification of BRIP1 germline mutations in BC patient with wild-type BRCA1 and BRCA2 suggests a major link between moderate penetrance of BC and BRIP1 mutation.[13,14,15,16] Based on these observations, we hypothesized that beyond its function as a DNA repair gene, BRIP1 plays a novel role in tumour cell invasion/metastasis. To providing a better understanding of the mechanisms that underpin BRIP1-mediated tumour cell invasion, this study has validated BRIP1 as a target gene that can be used to design efficient therapeutic strategies against BC
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