Metastatic breast cancer is the leading cause of breast cancer-related deaths. The underlying biology that drives metastasis is greatly unknown. Predictive signatures for poor prognosis breast cancer and high risk of metastasis are available and routinely employed in the clinical setting; however, these describe the risk of metastasis, not the underlying biologic drivers of metastasis while also lacking accompanying therapeutic approaches to block metastasis. Identifying genetic drivers of metastatic breast cancer is critical to the development of effective therapeutics to prevent and treat metastases; such a study has yet to be performed in primary human tissues. We hypothesize that specific genetic and/or genomic factors are required for breast cancer metastasis, and that some metastatic features exist within primary tumors destined to metastasize. Utilizing a Rapid Autopsy Protocol established at UNC Chapel Hill, we have collected over 170 metastatic tissues and performed RNA and DNA whole exome sequencing on a majority of these, with plans to complete sequencing in the near future. Aim 1 will define drivers of metastases through a statistical comparison of DNA copy number, point mutations, and RNA gene expression changes of 350 metastatic breast cancer tissues as compared to 1000 primary breast cancers previously published through the Cancer Genome Atlas. Aim 2 will determine the order in which these drivers of metastasis are acquired across molecular time. Genetic alterations shared at any frequency between metastases and primary breast cancers indicate ‘early’ alterations. We will validate the timing of these mutations by creating a phylogenetic tree for each autopsy patient, and then map each copy number and point mutation alteration onto the tree. Aim 3 will establish the signaling alterations of the supporting adjacent brain parenchyma to basal-like breast cancer tumors as measured by gene expression studies. Current literature from in vivo modeling suggests that significant changes to both breast cancer cells and the tumor microenvironment are critical for metastatic seeding and growth. Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapies. Comparing gene expression in adjacent non-malignant brain parenchyma to matched distant brain parenchyma both in human tissues and in two in vivo intracranial models will identify supporting microenvironment signals unique to the adjacent brain parenchyma, and these will be integrated with findings from Aims 1 and 2. It is our goal to identify genetic drivers of breast cancer metastasis, ultimately to define future therapeutic targets to help decrease mortality from breast cancer. Along with the superb environment at UNC Chapel Hill, exceptional mentoring by Dr. Perou and Dr. Anders, and a comprehensive training plan, this proposal will provide a critical foundation to build my future career as a physician-scientist in the field of cancer metastases.
|Effective start/end date||8/1/15 → 1/31/19|
- NIH National Cancer Institute (NCI)