Acquired genomic mutation is the fuel that drives cancer development, propagation, and resistance to chemotherapeutic drugs. Although the origin of much genomic mutation remains unknown, a new source of cancer-causing mutation has been uncovered in which APOBEC3B (A3B), a DNA cytosine deaminase of the innate immune system, catalyzes endogenous mutation. DNA cytosine deamination destroys Watson-Crick base pairing by producing uracils which template the insertion of adenines that complement thymines (G-to-A hypermutation) during subsequent rounds of DNA replication. A3B messenger RNA (mRNA) is upregulated in 65% of patient-derived primary breast cancer specimens and 90% of breast cancer cell lines. Tumors that over-express A3B have twice as many overall mutations as low A3B expressing tumors and are more likely to have mutations in TP53, the well-known tumor suppressor gene. This fellowship proposal will test the innovative hypothesis that small molecule inhibition of A3B will decrease the overall mutation rate in breast cancer cells. Methods include synthesizing small molecule inhibitory probes of A3B (Aim 1) and testing these inhibitors in mutation-reporting cell lines that enable the direct quantification of A3B-catalyzed mutagenesis (Aim 2). This proposed work will help to achieve the long-term goals of (i) demonstrating that A3B-catalyzed genomic mutation drives cancer progression and (ii) developing novel cancer therapeutics based on small molecule inhibitors of A3B. A3B is a near-perfect drug target because it is a non-essential enzyme in humans. The objective here is to deliver to the field the first chemical modulator of A3B, a tool that can be utilized by various laboratories to probe A3B-propagated cancers at pharmaceutically relevant concentrations. This goal is aligned with the mission of the NCI to support research aimed at developing state-of-the-art treatments for cancer.
Breast cancer is the second leading cause of cancer death among women and approximately 1-in-8 women in the United States will develop an invasive form of breast cancer during her lifetime. Recently, the human enzyme APOBEC3B was shown to be an endogenous driver of mutation in breast cancer. Because mutation enables cancer to metastasize and to develop chemotherapeutic resistance, the discovery and optimization of small molecule inhibitors of APBOEC3B may provide a foundation for the future development of state-of-the-art treatments for breast cancer.
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