Molecular and cellular basis for transformation associated with BRCA1-haploinsufficiency.

摘要

Individuals with inherited mutations in BRCA1 have a ~ 80% chance of developing breast and ovarian cancer within their lifetimes. Although BRCA1 function appears to be essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer development in individuals with mutations in BRCA1 is restricted to only a select few tissues. Moreover since loss of the remaining wild-type allele has been presumed to be a necessary and rate limiting event driving increased genomic instability and cancer formation, the tissue- and cell-type specific consequences of BRCA1 haploinsufficiency responsible for tumorigenesis remain poorly understood. Here we show that human mammary epithelial cells (HMECs), but not other cell types from individuals harboring deleterious mutations in BRCA1 (BRCA1mut/+), exhibit increased genomic instability and rapid telomere erosion in the absence of tumor suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and rapid telomere erosion in HMECs is mediated by misregulation of the NAD+-dependent deacetylase SIRT1 that leads to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a molecular basis for the cell and tissue specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.