Work in my lab is focused on identifying and understanding the molecular events associated with the initiation and progression of human cancer, particularly the role of abnormal cell proliferation and cell death. The clinical significance of these events in malignant and pre-malignant lesions of breast and ano-genital human tumors is of primary interest and our involvement in collaborative research provides a unique opportunity for translational of basic science discoveries to questions that can be posedin large, clinical and population-based studies.
The current model of carcinogenesis is that of a multi-step accumulation of genetic changes within cells that supplant normal controls on cell division and lead to increased cell proliferation. Abnormalities of the cell cycle in a highly proliferative cell population may then lead to additional molecular alterations. In fact, recent advances in our understanding of cell cycle mechanisms indicate that derangements in the cell cycle may not only contributeto uncontrolled cell growth but may be causal factors in the development of cancer. In collaboration with Drs. James Roberts, Janet Daling and Kathi Malone, we have identified associations between high levels of cyclin E, and low levels of the cell cycle inhibitor p27, with poor clinical outcome in a group of young women with breast cancer. The associations were most pronounced in women with lymph node negative disease, a finding that could greatly impact clinical management in this group of women.
We continue to investigate the role of aberrant expression of cell cycle proteins in pre-invasive breast and ano-genital tumors order to evaluate the role of cell cycle changes in the progression from in situ to invasive disease. We find significantly lower levelsof expression of cyclin E in in situ breast neoplasia than in invasive tumors, indicating a possible role in the transition to a malignant phenotype. We are currently examining patterns of expression of a set of cell cycle proteins which are representative of independent regulatory pathways (Cyclin D/Rb/p16 and Cyclin E/ p27), for the purpose of establishing a collection of markers in breast and ano-genital cancers, which together provide the most information about the status of cell cycle controls in individual tumors. Assessment of cell cycle regulators and their expression during the cell cycle will be facilitated by our development of multivariate flow cytometric assays in fixed tumor specimens.
Although we and others have successfully identified molecular markers of tumorigenesis using conventional approaches, single gene and protein changes are also unlikely to reflect the complexity of the molecular changes present in tumor cell populations. Using global approaches, made possible by developments in microarray technology and the identification of genes in the human genome project, we are now in a position to elucidate the molecular components, and the connections between the components, that coincide with the acquisition of malignant traits. We are conducting discovery projects using array CGH, SNP array, and expression array in studies of precursor and malignant lesions that will help to better understand, and respond appropriately to, the clinical heterogeneity of breast cancer.