BBB Seminar: Keshav K Singh
Intergenomic cross talk and its role in tumorigenesis
Keshav K. Singh,
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
Human mitochondrial DNA (mtDNA) encodes 13 proteins involved in oxidative phosphorylation (OXPHOS). In order to investigate the role of mitochondrial OXPHOS genes in breast tumorigenesis, we have developed a breast epithelial cell line devoid of mtDNA (r0 cells). Our analysis revealed that depletion of mtDNA in breast epithelial cells results in vitro in a tumorigenic phenotype, as well as breast tumorigenesis in a xenograft model. We identified two major gene networks which were differentially regulated between parental and r0 epithelial cells. The focal proteins in these networks include i) FN1 (fibronectin) and ii) p53. Bioinformatic analyses of FN1 network identified laminin, integrin and 5 of 6 members of peroxiredoxin whose expression was altered in r0 epithelial cells. In the p53 network, we identified SMC4 and WRN whose changes in expression suggest that this network may affect the chromosomal stability. Consistent with the above finding our study revealed an increase in DNA double strand breaks, and unique chromosomal rearrangements in r0 breast epithelial cells. Additionally, we identified tight junction proteins claudin-1 and claudin-7 in the p53 network. To determine the functional relevance of altered gene expression, we focused on detailed analyses of claudin-1 and -7 proteins in breast tumorigenesis. Our study demonstrated that i) claudin-1 and 7 were indeed down regulated in r0 breast epithelial cells, ii) down regulation of claudin-1 or -7 led to neoplastic transformation of breast epithelial cells, and iii) claudin-1 and -7 were also down regulated in primary breast tumors. Together, our study suggests that a multiple pathway involved in mitochondria-to-nucleus retrograde regulation contributes to transformation of breast epithelial cells and to breast cancer.
Host: Karl Johan Tronstad, Department of Biomedicine