Microbiome-Derived tRNA Q Modifications Mediate Breast Cancer Biology
Abstract
Breast cancer is not one disease but instead refers to a variety of types that each derive from distinct causes and therefore merit different treatments. In fact, a single breast tumor may be comprised of in situ cancer, limited to the local area in the breast, and invasive cancer that has spread to other breast tissues or areas of the body (see http://www.cancer.org). For treatments, it is critical to apply a variety of options that target a wide range of cellular mechanisms. It is crucial to develop new classes of molecules that target heretofore unexplored cellular mechanisms so that tumors not responsive to a particular treatment might be responsive to these new routes of therapy. This proposal will explore a new and previously under-appreciated avenue that links the breast cancer prevention and development with the gut microbes in the mammals. A fundamental step from DNA to protein is translation where the amino acid sequence information encoded by the gene is decoded by transfer RNAs (tRNAs). Each human cell type has well-defined levels and patterns of various tRNAs to allow regulation of protein synthesis. tRNAs are also heavily modified chemically; a specific form of modification is the queuosine (Q) that is derived from a micronutrient generated by our gut microbes. Our previous studies showed that all breast cancer tumors have higher levels of tRNA than normal breast tissues. tRNA overexpression has a unique pattern in breast cancer: some are present at very high levels, while others are present at moderate levels. We also found that a specific tRNA is an oncogene in breast cells. In our new study, we found that the tRNA Q-modification levels are very different in the breast tumors in living animals compared to normal breast tissues, suggesting that breast tumors can specifically use Q-modification for their own purposes. Our results suggest that tumors use tRNA properties to enable mis-regulation of some crucial proteins at the translational level. Aberrant tRNA properties may even originate the development of breast cancer. These results contrast the previous notions that tRNAs are just bystanders in cancer development and progression. This proposal will capitalize on our discoveries by identifying the function of tRNA Q-modifications in the regulation of gene expression in human breast cancer cells and in the breast tumor mouse models. Gut microbes have become increasingly important in the association of diet, lifestyles, and cancer biology. Our results will identify the potential of using tRNA Q-modified dependent gene expression in breast tumors as biomarkers, and of targeting these specific genes as a new route for breast cancer treatment. Ultimately, we aim to demonstrate the suitability of gut microbial dependent activities as a new route for the diagnosis and treatment of breast tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710039
Entities
People
- Jun Sun
Organizations
- United States Army
- University of Illinois at Chicago