Loss of BRCA1 in Normal Human Mammary Epithelial Cells Induces a Novel Mechanism of Senescence
Year: 2011
Type: dissertation
Abstract: Early events in BRCA1-associated tumorigenesis remain poorly understood. To understand the immediate consequences of BRCA1 loss of function, we modeled BRCA1 loss of function in vitro using normal primary human mammary epithelial cells (HMEC). We have found that in HMEC, loss of BRCA1 results in a novel type of senescence. Loss of BRCA1-induced senescence is not associated with DNA damage or p53 upregulation. We find that p53 protein levels are down regulated due to proteasome-mediated degradation. Although p53 levels are down regulated, we find that BRCA1 loss induced expression of a number of p53-dependent anti-oxidant genes. In particular we uncovered that SESN2, a p53 downstream target gene, inhibits loss of BRCA1 induced ROS and activates autophagy. In contrast to human fibroblasts, we found that loss of BRCA1 induced senescence is p53 independent, and can occur in the absence of ROS upregulation and autophagy induction.
Source: TSpace (University of Toronto)
Author: Salman Noor
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2559432408