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.
Breast cancer (BC) is the most common malignancy and second most common cause of cancer-related death in women, a clinical challenge exasperated by the lack of targeted therapies for metastasis, the most deadly component of BC. A significant barrier to successful treatment of metastatic disease involves the acquisition of dormant and chemoresistant phenotypes by disseminated tumor cells upon arrival to their metastatic niche. These cells are capable of reactivating proliferative programs to establish deadly metastatic recurrences years to decades after the initial implementation of therapy, making them one of the most clinically relevant targets in all of oncology. This study seeks to define the pathways critical to manipulating metastatic dormancy of BC cells, focusing specifically on the effect a novel lncRNA elicits on the epigenetic landscape of disseminated tumor cells. Successful completion of the proposed experiments will offer the foundation necessary to develop therapies that target molecular drivers vital to escape from dormancy in disseminated BC cells.
| Gooding, Alex J; Zhang, Bing; Gunawardane, Lalith et al. (2018) The lncRNA BORG facilitates the survival and chemoresistance of triple-negative breast cancers. Oncogene : |
| Gooding, Alex J; Zhang, Bing; Jahanbani, Fereshteh Kenari et al. (2017) The lncRNA BORG Drives Breast Cancer Metastasis and Disease Recurrence. Sci Rep 7:12698 |
