Since the inception of this project, a number of advances have been made. First and foremost, using animal models, this project was the first to demonstrate that inherited susceptibility genes exist that predispose individuals to the development of metastatic disease. Subsequently, we demonstrated that polymorphisms in the human orthologs of these genes were also associated with distant metastasis-free survival, demonstrating an important role for these genes in human disease. Further, analysis of the human data has shown that multiple susceptibility mechanisms exist for human breast cancer metastasis since polymorphisms that predispose women with estrogen receptor positive breast cancer were not associated with metastasis in estrogen receptor negative tumors and vice versa. Analysis of the TCGA data and breast cancer susceptibility data sets suggest the genes discovered in the metastasis susceptibility screens are not associated with predisposition for breast cancer nor are they frequently somatically mutated. These genes therefore represent a novel class of genes that are associated with efficiency with which tumor cells and the collaborating tumor-associated stroma proceed through the metastatic cascade. To date, using these methods, we have published 10 metastasis susceptibility genes and 6 metastasis-associated microRNAs. Eight additional genes have passed our initial validation studies and manuscripts are either in preparation or are approaching the preparation stage. Over the next four years we plan to continue mapping out the metastatic landscape by exploiting the technologies and strategies pioneered by the ENCODE project to further accelerate candidate gene discovery. We anticipate these methods will identify additional novel genes, implicate new molecular and cellular mechanisms associated with metastatic progression and potentially reveal important actionable targets for clinical prevention and/or management of advanced neoplastic disease. Intriguingly, our accumulating data is beginning to repeatedly implicate a few molecular and cellular systems as major contributors to metastatic susceptibility. Tumor autonomous susceptibility appears to be significantly associated with the adherins junction-cytoskeletal-LINC complex components. These structures, which connect the extracellular adhesion complexes to the inner face of the nuclear membrane, suggest that detection of extracellular microenvironmental cues that are mechanically transmitted to the nucleus may play an important role in tumor progression. Tumor non-autonomous susceptibility appears to be mediated primarily by the immune system, specifically cellular mediated responses. Further investigations are in progress to validate and extend these observations to provide greater understanding of how these mechanisms contribute to breast cancer progression. Finally, the systems genetics analysis in our mouse models is beginning to reveal transcriptional signals associated with metastatic susceptibility that are indicative of specific pathway activities. Importantly, many of these pathways have been targeted for drug development for other indications. FDA approved compounds exist for a number of these pathways, and may prove to be useful for metastasis prevention in conjunction with current adjuvant therapy standard of care. Validation of the utility of these compounds is currently underway in our animal model systems. If successful we anticipate that these compounds might rapidly be translated into the clinic due to pre-existing approval.
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