User:Nigel Crawford
Dr. Crawford's research seeks to define how genetic variation among individuals influences tumor progression and metastasis in prostate and breast cancer. The overall aim of his research is to identify, at the point of diagnosis, those individuals at greater risk for developing more aggressive cancers. With this knowledge, physicians could consider implementing more aggressive therapeutic regimens.
Prostate carcinoma is a common disease; for example, in 2007 in the United States, 220,000 men were diagnosed with this type of cancer, but only a small proportion of these men (typically ~30,000) will actually succumb to the disease. However, the clinical course of prostate cancer is variable, with some men presenting with more aggressive forms of the disease at the time of diagnosis. Genetic predisposition plays an important role in prostate cancer development, and it has been estimated that 5-10 percent of cases have a familial component.
These observations form the basis of the research performed in Dr. Crawford's laboratory. His studies explore whether individual genetic variation promotes the development of prostate cancers that are more prone to metastasizing and resistant to therapeutic interventions. He characterizes the differences in tumor growth and metastasis that result when germline polymorphisms are introduced, through selective breeding, into mice prone to developing prostate cancer. His laboratory uses a well-characterized transgenic mouse model of prostate tumorigenesis called TRAMP (for "transgenic adenoma mouse prostate"). TRAMP mice are crossed with a strain of recombinant inbred mouse called the "Collaborative Cross"; these mice incorporate a broad spectrum of allelic variants that are present in a number of inbred strains, and it is anticipated that they will be widely used in the study of complex traits.
Using a statistical method for studying genetic variation called quantitative trait locus (QTL) mapping, Dr. Crawford analyzes DNA from the offspring of TRAMP and Collaborative Cross mice. His goal is to identify multiple sites, called modifier loci, in the mouse genome that drive the development of more aggressive forms of tumorigenesis and metastasis. The researchers in his laboratory use a combination of methodologies to identify individual candidate genes at each modifier locus. The role of these candidate modifier genes in tumor progression and metastasis is explored in human prostate tumor progression through a combination of functional analyses and epidemiological association studies.
In addition, Dr. Crawford's laboratory is investigating the role of the RRP1B gene in tumor progression and metastasis in breast cancer. By using a well characterized transgenic model of mouse mammary tumorigenesis, RRP1B was identified as a candidate modifier QTL gene for metastasis efficiency. Subsequent experimentation using in vitro and in vivo modeling in mice demonstrated that activation of the RRP1B gene suppresses tumor growth and metastasis, yielding a gene expression signature that can be accurately used to predict survival in human breast cancer. Dr. Crawford was part of a research consortium demonstrating that the human RRP1B gene contains variants associated with markers of metastasis and survival in multiple breast cancer epidemiological cohorts.
In recent breast cancer studies, Dr. Crawford has focused on the function of RRP1B, which had previously been a poorly characterized protein. His analyses have explored the interaction of RRP1B with other proteins, particularly with a number of nucleosome-binding proteins that are potent modulators of gene expression and chromatin structure. The laboratory is using chromatin immunoprecipitation and "next-generation" DNA sequencing methodologies to identify promoter sequences that bind RRP1B. Dr. Crawford expects these studies to provide greater insight into the function of this metastasis efficiency modifier and how dysregulation of RRP1B gene expression has such potent effects on global gene expression.
