Inhibiting Mutation to Prevent and Treat Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Floyd Romesberg, Ph.D. -
Award Cycle: 2010 (Cycle 16) Grant #: 16IB-0037 Award: $63,021
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2010)

A major challenge in fighting breast cancer is that all individual cancers are different; however, all forms of cancer, including breast cancer, begin and progress the same way, with the mutation of our DNA. Some of these mutations are inherited, as in the case of mutations in the BRCA1 and BRCA2 genes. However, even in these cases, additional mutations must be acquired for the cell to become cancerous. Mutations also underlie metastasis, as well as drug resistance. Remarkably, mutation is not a passive process, and specific biochemical pathways are responsible for introducing mutations to the genome in response to DNA damage. The single known pathway of induced mutation has been studied intensively by many different research groups. However, we recently identified a novel biochemical pathway of DNA damage-induced mutation in yeast, a simple model organism that responds to DNA damage in much the same way as human cells. This appears to be the major pathway of induced mutation in yeast and involves the enzyme ribonucleotide reductase, which supplies the building blocks of DNA (dNTPs), and a polymerase enzyme that normally copies DNA without errors. We demonstrated that yeast treated with the ribonucleotide reductase inhibitor and cancer chemotherapeutic drug, hydroxyurea, were less likely than untreated cells to make mutations following exposure to the DNA damaging agent, UV light.

Our project is designed to extend these observations in yeast to human cells in the context of mutation pathways leading to breast cancer. We will examine cultured human breast cells for DNA-damage dependent changes in the expression and activity of ribonucleotide reductase. Our work in yeast indicates that the anti-mutation effect of inhibiting ribonucleotide reductase is mediated specifically through a regulatory subunit of the enzyme. We will use gene silencing to “knockdown” expression of the two regulatory subunits of human ribonucleotide reductase and examine the role of each individually on DNA-damaged induced mutation.

From the perspective of breast cancer biology and medicine, these mutation concepts represent a radically new view of disease development, progression, and most importantly, prevention and treatment. The CBCRP-funded research represents our next step toward developing an entirely new approach to preventing and treating breast cancer, not by treating the phenotype of the cell, but by preventing the acquisition of the mutations that are necessary and sufficient for disease progression.