The proposed study is to investigate the roles of long non-coding RNAs (lncRNAs) in the DNA damage response (DDR) and breast cancer. As a primary anti-cancer barrier in early tumorigenesis, the DDR involves a complicated and entangled network of processes that sense and repair DNA damage to maintain genomic integrity, in which lncRNAs, a novel class of regulatory RNA molecules, may play important roles. In this proposed study, I found strong evidence that lncRNAs were regulated by ATM, an essential kinase in the DDR. Two of such lncRNAs, termed JANDA (Jade1 associated ncRNA DNA damage activated) and MANDS (Mfhas1 associated ncRNA DNA damage suppressed), have significant impacts in chromatin remodeling and breast tumorigenesis and metastasis. I propose that DDR induced-JANDA is a key functional link that connects the DDR to histone H4 acetylation, and DDR suppressed-MANDS serves as a tumor suppressor by targeting Mfhas1, an ROCO protein beyond a candidate oncogene, and dysregulation of JANDA may contribute to breast tumor progression and metastasis. In Aim 1, I will explore the molecular mechanism of JANDA and MANDS in the DDR. I will also determine global regulation of gene expression by JANDA and MANDS and their roles in the DDR and DNA repair. My preliminary data showed JANDA was overexpressed in human breast tumors and may have pro-oncogenic property in breast cancer initiation, so in Aim 2 I will evaluate the expression level of JANDA and H4 acetylation in breast cancer tissues and in response to oncogenic stress in mammary cells. JANDA may serve as a novel negative prognostic factor and exhibit pro-metastatic activity in HER2 type tumors, so in Aim 3, I will assess the role of JANDA as a metastasis promoter in breast cancer and detect the effects of silencing JANDA in trastuzumab-resistant HER2 type tumors. Lastly, I will evaluate JANDA as a potential therapeutic target in breast cancer. This proposed study will provide me with the best opportunity to start up my independent career in academia. My long term goal is to explore the contribution of non-coding RNAs in health and disease. To that end, I will continue enhancing my technical skills in molecular biology, cancer biology, epigenetics, mouse engineering and manipulation, and expanding my expertise in cancer genomics, stem cell biology and translational biology. For my career development, I will learn to improve my skills on managing laboratory, mentoring postdoctoral fellows and students, scientific writing and presentation and establishing new collaborations. The Department of Cancer Biology at MD Anderson Cancer Center has a long history of being a leader in the field of translational cancer research, where I am able to translate state-of-art studies into clinical applications. With the support of K99/R00, I will be able to 1) complete the proposed studies and explore novel ideas that arise from preliminary studies, 2) search for novel strategies to sensitize human breast cancer cells in chemotherapy and radiotherapy, 3) establish my independent research team and expand my network into DNA damage, non-coding RNA and breast cancer fields.