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Mutation of Breast Cancer Cell Genomic DNA by APOBEC3B

Principal Investigator: BURNS, MICHAEL B
Institution Receiving Award: MINNESOTA, UNIVERSITY OF, TWIN CITIES
Program: BCRP
Proposal Number: BC101124
Award Number: W81XWH-11-1-0014
Funding Mechanism: Predoctoral Traineeship Award
Partnering Awards:
Award Amount: $82,654.56


PUBLIC ABSTRACT

My research proposal offers a unique and innovative approach to understanding the molecular details of breast cancer development. With the knowledge gained from my work, a new target for both breast cancer prevention and treatment could be uncovered. We know that in order for a cell to become cancerous, the cellular DNA needs to be mutated multiple times. Unfortunately, aside from known environmental agents, such as the chemicals in tobacco smoke, the sources of these mutations remain poorly defined. Seven years ago, my mentor, Dr. Reuben Harris, discovered a new class of DNA mutating proteins, the APOBEC3 (A3) proteins. Normally, members of the APOBEC family of proteins are key players our immune system's ability to respond to infections. These proteins mutate harmful viral DNA, rendering it incapable of damaging our cells. However, while there are certainly instances in which these proteins are beneficial, what happens when things go wrong?

Several lines of evidence implicate APOBEC3B as a causative agent in breast cancer: (1) APOBEC3B is a potent DNA mutating protein, (2) APOBEC3B is found at much higher than normal levels in many breast cancers, (3) related proteins are known to cause different types of cancer, and (4) mutations seen in breast cancers have the same molecular fingerprint as those made by APOBEC3B. I hypothesize that the correlation between breast cancer and APOBEC3B is more than just coincidence. I am prepared to demonstrate that this recently characterized protein mutates the DNA of breast cancer cells and drives the genesis of breast cancer. Furthermore, I propose that the continued mutating activity of APOBEC3B contributes to breast cancer progression, diversification, and resistance to therapy. The anticipated outcome of my research is the identification of pro-cancerous enzyme, which will set the stage for the development of drugs that prevent breast cancer and cripple it in a way that prevents it from escaping current anti-cancer therapy.

I am currently working toward obtaining a Ph.D. in molecular and cancer biology. My education will prepare me for a career as a breast cancer scientist in an academic research center. This grant will help me to achieve this goal. Primarily, it will provide resources to facilitate the proposed groundbreaking research while also furthering my education and experience in the field of breast cancer research. The secondary benefits include the boost to my resume generated by the competitive acquisition of funding as well as authoring and publishing my research.

The research project itself directly contributes to my establishment as a breast cancer researcher in that it is a novel approach to uncovering how breast cancer works and it opens the door to novel therapeutic opportunities. My work has the potential to both prevent and possibly cure some breast cancers. If I am correct in hypothesizing that APOBEC3B is the cause of some breast cancers and that it promotes cancer progression and resistance to therapy, the next step is to develop drugs that inhibit mutagenic activity. In fact, I am working with several members the lab to perform preliminary tests validating compounds that can inhibit the DNA mutating activity of this protein. APOBEC3B inhibitors have the distinct advantage of fighting cancer prior to onset and following detection. No other single treatment has all of these benefits with so few risks. Thus far, several APOBEC3 inhibitors have been identified, and many more are in our development pipeline. As an additional bonus, APOBEC3B inhibitors are likely to have very low toxicity, as there are several populations of humans that do not have the APOBEC3B gene who are entirely normal. We anticipate a clinical application of this work in as few as 5 years.

This work will lay the foundation for a new understanding of how breast cancer can be generated from a normal cell into a tumor and then progress from a tumor into a life-threatening, drug-resistant disease. Understanding the mechanism of action at each of these phases provides opportunity for treatments at each phase of cancer progression. While much of the preliminary data from the Harris lab provides the "smoking gun" to implicate APOBEC3B in breast cancer, my work will define that role explicitly and justify the creation of the next (and hopefully final) generation of breast cancer therapeutics.