A recently discovered facet of the breast cancer susceptibility gene BRCA1 reveals a mechanism linking mutation of BRCA1 to formation of large blood vessels needed to support cancer progression.
The findings demonstrate that, in addition to an impaired DNA damage response associated with cancer initiation, mutation of BRCA1 is also linked to manipulation of the tumor microenvironment. The research appears in the July issue of Cancer Cell, published by Cell Press.
Mutations in the breast cancer susceptibility gene BRCA1 account for up to 50% of hereditary breast cancers. BRCA1 is known to serve as a tumor suppressor by regulating DNA damage repair and maintaining genomic stability. Although the mechanism is not fully understood, reduced BRCA1 expression is also often correlated with accelerated growth and progression of breast tumors and with increased tumor blood vessel formation. In order to better understand the link between BRCA1 and tumor progression, Dr. Wen-Hwa Lee and colleagues from the Department of Biological Chemistry at the University of California, Irvine, designed a series of experiments to search for genes that are regulated by BRCA1.
The researchers used microarray analyses to identify genes repressed by BRCA1 or a related tumor suppressor, CtIP, in mammary epithelial cells (MECs). Among the 12 genes inhibited by BRCA1 or CtIP was the gene for a secreted factor, called ANG1, that enhances blood vessel growth and maturation. The researchers found that a defect in a repressor complex formed by BRCA1, CtIP, and another known transcription repressor, ZBRK1, released the gene for ANG1 from repression and promoted survival of neighboring blood vessel cells and formation of capillary-like structures. Further studies demonstrated that mouse mammary tumors deficient in BRCA1 display high levels of ANG1 expression, prominent vascularization, and accelerated growth.
"Our study finds that BRCA1 possesses a role in tumor suppression beyond maintaining genomic stability by regulating intercellular signaling within the tissue microenvironment. This view will extend BRCA1's tumor suppression function to the surroundings that influence the fate of neighboring cells and fortify the pathogenic relevance of its defect to neoplastic growth," concludes Dr. Lee.