Abstract
BRIP1 is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1 and plays an important role in BRCA1-dependent DNA repair and DNA damage–induced checkpoint control. Recent studies implicate BRIP1 as a moderate/low-penetrance breast cancer susceptibility gene. However, the phenotypic effects of BRIP1 dysfunction and its role in breast cancer tumorigenesis remain unclear. To explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells, we generated BRIP1-knockdown MCF-10A cells by short hairpin RNA (shRNA)-mediated RNA interference and examined its effect in a three-dimensional culture model. Genome-wide gene expression profiling by microarray and quantitative RT-PCR were performed to identify alterations in gene expression in BRIP1-knockdown cells compared with control cells. The microarray data were further investigated using the pathway analysis and Gene Set Enrichment Analysis (GSEA) for pathway identification. BRIP1 knockdown in non-malignant MCF-10A mammary epithelial cells by RNA interference induced neoplastic-like changes such as abnormal cell adhesion, increased cell proliferation, large and irregular-shaped acini, invasive growth, and defective lumen formation. Differentially expressed genes, including MCAM, COL8A1, WIPF1, RICH2, PCSK5, GAS1, SATB1, and ELF3, in BRIP1-knockdown cells compared with control cells were categorized into several functional groups, such as cell adhesion, polarity, growth, signal transduction, and developmental process. Signaling-pathway analyses showed dysregulation of multiple cellular signaling pathways, involving LPA receptor, Myc, Wnt, PI3K, PTEN as well as DNA damage response, in BRIP1-knockdown cells. Loss of BRIP1 thus disrupts normal mammary morphogenesis and causes neoplastic-like changes, possibly via dysregulating multiple cellular signaling pathways functioning in the normal development of mammary glands.
Highlights
Breast cancer is one of the most common epithelial malignancies among woman worldwide
Loss of BRIP1 Causes Abnormal Acinar Morphogenesis To determine whether BRIP1 knockdown affects the formation of polarized spherical acini, mammary epithelial cells were grown and monitored in 3D culture
We revealed that the BRCA1-interacting helicase BRIP1 has important roles in promoting normal acinar morphogenesis and loss of BRIP1 disrupts acinar formation possibly through the dysregulation of multiple celluler signaling pathways
Summary
Breast cancer is one of the most common epithelial malignancies among woman worldwide. One in ten women will develop breast cancer during their lifetime in industrialized countries. The majority of breast cancers are sporadic in origin, an appreciable fraction is caused by inherited predisposition. Germline mutations in the two major susceptibility genes for breast cancer, namely BRCA1 and BRCA2, confer a 60–85% lifetime risk of breast cancer but account for only about 20% of familial breast cancer cases [1,2,3,4,5,6,7]. Several other breast cancer susceptibility genes, which show low-to-moderate penetrance, have been identified. BRIP1 is one of these genes and truncating mutations confer a 2-fold increase in breast cancer risk [8], [9]
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