Novel mechanism of BRCA1 mutation-based tumorigenesis elucidated.(breast cancer development)

2003 JAN 2 - (NewsRx.com & NewsRx.net) -- Beth Israel Deaconess Medical Center, Massachusetts, researchers have described "a novel pathogenic mechanism whereby mutations in BRCA1, via their interaction with estrogen receptor-alpha, could promote tumorigenesis through the hormonal regulation of mammary epithelial cell proliferation and impaired vascular endothelial growth factor function, which may lead to cancer growth and angiogenesis."

"Mutational inactivation of BRCA1 confers increased risk for breast cancer. However, the underlying basis for the breast tissue-restricted, tumor-suppressive properties of BRCA1 remains poorly defined," wrote H. Kawai and colleagues.

In a paper published in Oncogene, they "show that BRCA1 and the estrogen receptor alpha (ER-alpha) modulated vascular endothelial growth factor (VEGF) gene transcription and secretion in breast cancer cells."

"ER-alpha interacted in vitro and in vivo with BRCA1, and this interaction was mediated by the AF-2 domain of ER-alpha and two domains of BRCA1, the amino-acid residues 1-306 and 428-683," the researchers reported (Direct interaction between BRCA1 and the estrogen receptor regulates vascular endothelial growth factor (VEGF) transcription and secretion in breast cancer cells. Oncogene, 2002;21(50):7730-7739).

"Endogenous interaction of ER-alpha with BRCA1 was observed in normal MCF-10A breast epithelial cells and in breast cancer cells (MCF-7 and T47D), and this interaction was significantly reduced in the presence of estrogen. Furthermore, ER-alpha induced activation of VEGF gene transcription, using human VEGF promoter-luciferase reporter constructs," Kawai's group said.

"The AF-2 domain of ER-alpha was also ...