Jim Shull

Estrogens are inextricably implicated in the etiology of breast cancer.  The primary goals of our research group are to utilize the ACI rat model of 17β-estradiol (E2)-induced mammary cancer to identify novel genetic determinants of breast cancer susceptibility and to define the molecular mechanisms through which estrogens contribute to development of breast cancer. Whereas ACI rats are highly and uniquely susceptible to E2-induced mammary cancer, the Copenhagen (COP) and Brown Norway (BN) rat strains are resistant to mammary cancer development when treated with E2.  In genetic crosses between ACI and COP or BN rats, we have mapped several genetic determinants of mammary cancer susceptibility within the rat genome, designated Emca1 through Emca9. Research currently underway is focused on high resolution mapping and identification of the mammary cancer susceptibility genes that reside within these Emca loci.  We hope to then determine how these genes influence mammary cancer development and to evaluate the impact of these same genes on breast cancer risk in human populations.  Knowledge regarding the identities of these genes should reveal novel insight into the mechanisms through which estrogens contribute to breast cancer development.

Mammary cancers that develop in E2 treated ACI rats exhibit non-random and recurring patterns of chromosome copy number changes.  A second project underway in our group is focused on defining the role of genome instability in the genesis of E2-induced mammary cancer. We also hope to define the mechanism through which E2 induces genome instability in this rat model.