"? DESCRIPTION (provided by applicant) Over 90% of breast cancer (BC)-related deaths are attributed not to the direct growth of the primary tumor, but rather to the spread of these malignant cells to distant organs, a process known as metastasis. Despite decades of investigation, a complete understanding of the molecular forces vital to metastasis remains incomplete, a gap in knowledge that has hindered the development of therapeutics that specifically target metastatic lesions. Contributing to this failure is the ability of disseminated tumor cells to enter a state of dormancy upon arrival to their metastatic microenvironment, wherein they remain viable and resistant to many standard-of-care chemotherapies, especially those that target rapidly dividing cells. Indeed, these cells do not persist indefinitely in a stat of dormancy, as they possess the capability to reinstate proliferative programs to provide the source for deadly metastatic recurrences years after clinical remission is initially achieved. The pathways underlying the initial instatement of dormancy and, more importantly, those crucial to subsequent escape from dormancy, are poorly understood and must be further interrogated in an effort to develop maintenance therapies that specifically target these undetectable cells. Since genetic changes are, by nature, less prone to arise and be selected for in a non-proliferative niche, it is natural to assume that dormant phenotypes are most susceptible to epigenetic alterations. We therefore seek to delineate epigenetic alterations critical to manipulating metastatic BC dormancy. In doing so, we will focus on a specific member of an emerging class of RNA, long-noncoding RNA (lncRNA), that has been shown to induce global changes in chromatin modification patterns and confer metastatic features to a dormant BC cell line. Using powerful epigenomic techniques in an established model of BC dormancy, we will map the epigenetic landscape modified by this lncRNA in concert with its molecular binding partners. These experiments will provide crucial insight into the mechanisms underlying BC dormancy both dependent and independent of this pro-metastatic lncRNA, thereby establishing the molecular foundation necessary to develop therapies that improve long-term outcomes for BC patients. " |