| dc.description.abstract | Breast cancer is the most common cancer in women, affecting approximately one in eight women during their lifetime. There is increasing evidence that genomic instability is a precursor to breast cancer progression from initial hyperplasia to invasive cancer. Previous studies have demonstrated that individuals who carry mutations in the critical DNA damage repair proteins, BRCA1 and BRCA2, are more likely to develop high-grade ductal carcinoma in situ (DCIS), which is characterized a neoplastic mammary lesion that is confined to the ductal-lobular system of the breast. In addition to the higher occurrences of DCIS in these individuals, they are more likely to progress from DCIS to the more malignant invasive ductal carcinoma (IDC). Here we identify SIM2s (Singleminded-2s; a member of the bHLH/PAS family of transcription factors) as a novel member of the homologous recombination (HR) pathway of DNA damage repair. In this study we show that SIM2s is stabilized through interaction with ATM, which leads to phosphorylation of SIM2s in response to dsDNA damage. Once stabilized, SIM2s interacts with members of the HR pathway and enhances RAD51 recruitment to the site of DNA damage. Inhibition of this process through the mutation of SIM2s at the ATM recognition site (S115) or loss of SIM2s leads to a significant decrease in dsDNA repair via HR and prolonged presence of dsDNA breaks. Moreover, we found that SIM2s is necessary to maintain replication fork stability during replication stress, with loss of SIM2s resulting in a significant increase in replication fork collapses, leading to further unresolved dsDNA breaks.
Finally, we found that loss or mutation of SIM2s leads to an epithelial mesenchymal transition (EMT) that is characterized by a decrease in E-cadherin and induction of the basal marker, K14. In addition, we observed increased invasion and metastasis using both our DCIS progression model cell line and in xenograft models. Together, these results identify SIM2s as a novel player in the DNA damage repair pathway and suggest that loss of SIM2s connects DCIS progression to IDC through increased genomic instability, EMT, and metastasis. | en |
