Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells.
Cumulative evidence indicates that breast cancer-associated gene 1 (BRCA1) participates in DNA damage repair and cell-cycle checkpoint control, serving as a tumor susceptibility gene to maintain the global genomic stability. However, whether BRCA1 has a direct role in cell proliferation and differentiation, two key biological functions in tumorigenesis, remains unclear. Here we demonstrate BRCA1 mediates differentiation of mammary epithelial cell (MEC) for acinus formation by using the in vitro 3D culture system. Reduction of BRCA1 in MEC by RNA interference impairs the acinus formation but enhances proliferation. Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-binding domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes. Consistently, depletion of BRCA1 up-regulates the gene expression for proliferation but down-regulates that for differentiation. Moreover, application of the medium conditioned by differentiating normal MEC can reverse the phenotypes of differentiation-defective breast cancer cells bearing reduced BRCA1 functions. Our observation implies BRCA1 is involved in secretion of certain paracrine/autocrine factors that induce MEC differentiation in response to extracellular matrix signals, providing, in part, an explanation for the etiological basis of either sporadic or familial breast cancer due to the loss or reduction of BRCA1.
Furuta
Saori
S
Department of Biological Chemistry, College of Medicine, University of California, Irvine, CA 92697, USA.
Jiang
Xianzhi
X
Gu
Bingnan
B
Cheng
Eric
E
Chen
Phang-Lang
PL
Lee
Wen-Hwa
WH
D000256:Adenoviridae / Q000235:genetics; D019313:BRCA1 Protein / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D005822:Genetic Vectors; D006801:Humans; D021621:Imaging, Three-Dimensional; D042361:Mammary Glands, Human / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D015854:Up-Regulation
D019313:BRCA1 Protein; D017077:Culture Media, Conditioned; D016160:Retinoblastoma Protein; D012313:RNA