Molecular Pathogenesis of Breast and Ovarian Cancer
Our laboratory is dedicated to the study of processes that, when defective, allow human cells to develop malignant characteristics. These processes are, in part, controlled by tumor suppressor loci. We continue to concentrate our efforts on a subset of these loci, all of which exert their functions in the nucleus. Some participate in the control of cell proliferation, others in the control of genome integrity, and still others in mechanisms that underlie the ability of cells to thrive in low-oxygen environments and under other stresses. Based on some unexpected results, we have extended our work over the past two years to explore the events that give stem cells of certain tissues the ability to self-renew.A fraction of our effort is dedicated to understanding the genetics of breast and ovarian cancer development. In particular, we are studying the in vivo biochemical and biological functions of four genes - BRCA1, BRCA2, BACH1, and BARD1 - which encode large nuclear proteins that interact specifically with one another. At least three and likely all four of these proteins are products of tumor suppressing loci. Together, they function as parts of large nuclear complexes that participate in the response of cells to DNA damage, and perhaps in other basic functions as well. When BRCA1, BARD1, or BRCA2 is rendered defective by germline mutation in females, tumor development develops at higher than normal frequencies in the breast and the ovary. A major segment of our ongoing work is aimed at trying to understand how, in biochemical terms, BRCA1 and BRCA2 perform their tumor suppressing effects and why, in the case of BRCA1, these effects are detected in the cells of women but not men.