Loss of the BRCA1-interacting helicase BRIP1 results in abnormal mammary acinar morphogenesis

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. In this study, we used the three-dimensional culture of human mammary epithelial cells as a model of mammary gland morphogenesis, to explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells. 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. BRIP1-knockdown cells showed dysregulation of multiple signaling pathways and tumor-associated genes including SATB1, a key transcriptional regulator that promotes tumor growth and metastasis of breast cancer. These results suggest that BRIP1, by regulating multiple tumor-associated genes and signaling pathways, plays important roles not only in the development of mammary glands but also in the neoplastic conversion of mammary epithelial cells.The 22nd Biennial Congress of the European Association for Cancer Researc