The Replication Stress Response Defect Is Associated With Tumor-Initiating Cell Formation

Breast cancer is the most prevalent cancer in women and early diagnosis of breast cancer greatly improves successful treatment and survival rate. Therefore, it is essential to expand current understanding in breast tumorigenesis in order to find specific treatment to target breast cancer in its precancerous or earliest stage. To date, two important observations have been made in terms of precancerous and early breast caner development. First, replication stress response (RSR), also referred to as intra-S checkpoint, serves as a barrier to prevent the occurrence of precancerous lesions and tumorigenesis. When normal cells encounter DNA damages resulting from oncogenic stress, these damages will trigger RSR and provoke cell cycle arrest for repairing damaged DNA or force damaged cells to undergo senescence or apoptosis. However, when RSR is defective, the cells with DNA damage will be able to break the barrier and transform to cancer cells. Second, tumor-initiating cells, which possess stem cell-like properties, are also required for tumorigenesis. Tumor-initiating cells are on the top of the tumor development hierarchy. Therefore, they form in the early stage and then differentiate themselves into nontumorgenic cancer cell to give the heterogeneity of tumor. Even though both processes strongly regulate tumorigenesis, it remains unclear whether defective RSR is associated with tumor-initiating cell formation. To gain insight into breast tumorigenesis from this aspect, RSR-intact cells were given oncogenic stress by exogenous expression of cyclin E, a major oncogene in breast cancer. Once the cells encounter oncogenic-stress-induced DNA damage, several key RSR genes, such as ataxia telangiectasia and Rad3 related (ATR), are then suppressed in order to allow damaged cells to escape from senescence. By measuring the expression changes of transcriptional landscape in RSR-deficient model system, the molecular profile of RSR defective cells are more similar to breast mammary stem cell and breast tumor-initiating cells. Furthermore, the RSR defective cells increase ALDH1, a marker of normal and malignant human mammary stem cell, and increase the ability of mammosphere formation, an indicator of self-renewal property of mammary epithelial stem cells.Importantly, we have also identified EGFR/MEK1 signaling as a key pathway that renders RSR defective cells the ability to escape from senescence or evade apoptosis and acquire tumor-initiating properties. Our findings not only provide insight into the RSR defective function network and the association between RSR defect and tumor-initiating cell formation in early breast cancer development, but also identify the key pathway for breast cancer target therapy and prevention. Citation Format: Curtis Chun-Jen Lin, Hui Dai, Shiaw-Yih Lin. The replication stress response defect is associated with tumor-initiating cell formation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2014-354