Abstract
DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized ‘normal-like’ breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.
Highlights
The process of tumorigenesis involves several genotoxic insults such as mutations, replicative stress and genetic instability [1,2,3]
In order to address if DNA damage associated cellular markers possess any correlation with the risk for invasive breast cancer, we investigated 3 cohorts of women: i) women with histologically normal breast tissue, ii) women with histological changes of increased risk (LCIS, ADH, atypical lobular hyperplasia (ALH)) but without a personal history of breast cancer and iii) women with ductal carcinoma in situ (DCIS) (Table 1)
We report that activation of DNA damage response (DDR) appears to be a robust barrier to mammary tumorigenesis, and that suppression of AKT-mTOR pathway may be involved in maintenance of this barrier
Summary
The process of tumorigenesis involves several genotoxic insults such as mutations, replicative stress and genetic instability [1,2,3]. Whereas oncogene induced aberrant replication evokes activation of ATR and chk both of these mechanisms together lead to the accumulation of phosphorylated form of cH2AX, a well recognized marker of DNA damage In turn this results in cell cycle arrest or cell death in p53 dependent manner, creating a selection pressure against early tumor progression by removing the aberrant cells [5]. Various components of DDR barrier such as cH2AX, pChk, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis have been found to be activated in precancerous lesions from organs such a lung, colon, and skin suggesting the protective role of DDR in the process of neoplastic transformation [3] These studies have reported tissue specific differences in the levels of proliferation and cell death/senescence in various stages of neoplastic transformation [3]. Since DDR studies to date have been largely confined to tumor models, an additional objective of this study was to examine the mechanisms behind DDR activation in a non-tumor context, looking at immortalized mammary epithelial cells
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