A series of critical pathways are responsible for the detection, signaling and restart of replication forks that encounter blocks during S-phase progression. Small base lesions may obstruct replication fork progression and processing, but the link betw...

Follicular lymphoma (FL), the most common indolent subtype of non-Hodgkin's lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from time of diagnosis. However, in 20-60% of FL patients, transformation to agg...

Production of mitochondrial reactive oxygen species and integrity of mitochondrial DNA (mtDNA) are crucial in breast cancer progression and metastasis. Therefore, we evaluated the role of mtDNA damage in breast cancer by genetically modulating the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) in the PyMT transgenic mouse model of mammary tumorigenesis. We generated mice lacking OGG1 (KO), mice overexpressing human OGG1 subunit 1alpha in mitochondria (Tg), and mice simultaneously lacking OGG1 and overexpressing human OGG1 subunit 1alpha in mitochondria (KO/Tg). We found that Tg and KO/Tg mice developed significantly smaller tumors than KO and wildtype mice after 16 weeks. Histological analysis revealed a roughly two-fold decrease in the incidence of lung metastases in Tg mice (33.3%) compared to wildtype mice (62.5%). Furthermore, lungs from Tg mice exhibited nearly a 15-fold decrease in the average number of metastatic foci compared to WT mice (p<0.05). Primary tumors isolated from Tg mice also demonstrated reduced total and mitochondrial oxidative stress, diminished mtDNA damage, and increased mitochondrial function. Targeting hOGG1 to the mitochondria protected cells from mtDNA damage resulting in downregulation of HIF-1alpha and attenuated phosphorylation of Akt. Collectively, we demonstrate proof of concept that mtDNA damage results in breast cancer progression and metastasis in vivo. Moreover, our findings offer new therapeutic strategies for modulating the levels of mtDNA repair enzymes to delay or stall metastatic progression.

Therapy resistance and poor outcome in prostate cancer is associated with increased expression of Cyclin D1. Androgens promote DNA double strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this...

Tumor-associated macrophages (TAMs) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulate within metastatic sites to promote the invasion and growth of tumor cells. Src Kinase Associated Phos...