|Department Affiliations||Departments of Pathology and Oncology|
|SOM Address||304 Cancer Research Building II|
Our laboratory investigates the molecular biology of breast cancer and lung cancer, emphasizing aspects that have potential clinical significance. Current areas of emphasis include molecular classification of cancers, genetic instability in cancer, and functional changes in cancers related to cell-cell interactions and cellular metabolism.
The molecular classification of cancers has attracted widespread interest because routine microscopic examination of tissues by the pathologist frequently cannot predict the biology of cancers. Much of our previous work focused on classifying cancers according to chromosomal changes, but we are increasingly using methods that measure gene expression to classify cancers. We believe that mRNA levels alone will not provide a comprehensive molecular profile of cancers and measurements of protein levels and protein activation status may be needed to accurately determine the status of various key pathways in cells. This work involves a variety of laboratory methods, because of the quantities of data generated in projects of this nature (using gene expression arrays and tissue microarrays), there is an increasingly important role for effective bioinformatics and statistical analysis.
Our work on chromosomal changes in cancers led us to recognize that most cancers have an intrinsic instability of their genome. We have recently characterized chromosomal instability in breast cancer, recognizing that there are at least two different classes of breast cancers, based on different levels of instability. Those cancers with high levels of instability have mitotic spindle damage checkpoint defects, and we are investigating the possible role of known checkpoint genes in causing these defects.
Our work on proteins that mediate cell-cell interactions or cellular metabolism is an extension of our work on gene expression and cancer classification. We have found that a significant number of proteins that mediate cell-cell communications (e.g., e-cadherin, connexins) have decreased expression in breast cancer and lung cancer. We are now undertaking investigations to determine the mechanism of the decreased expression and the functional significance of this decreased expression in the cancer cells. Altered expression of proteins that mediate cellular metabolism is interesting, not only because of implications regarding the pathogenesis of cancer, but also because of potential therapeutic opportunities. Our gene expression and protein activation studies are finding that the alterations in cellular metabolism affect pathways for glucose metabolism as well as fatty acid metabolism. Recently, we found that a small molecule compound that inhibits the enzymatic function of fatty acid synthase is an effective treatment for mesothelioma xenografts and we are further investigating this compound for treatment of lung cancer.
- Gabrielson, E.W., Penn, M.W., Testa, J.R., and Kuhajda, F.J. Increased fatty acid synthase is a target for treatment of mesothelioma. Clinical Cancer Research 7: 153-157, 2001.
- Yoon, D.S., Wersto, R.P., Zhou, W., Chrest, F.J., Kwon, T.K., Gabrielson, E., Variable Levels of Chromosomal Instability and Mitotic Spindle Checkpoint Defects in Breast Cancer, Am J Pathology 161: 391-398, 2002.
- Parmigianni, G., Garrett, E.S., Anbazhagan, R., and Gabrielson, E. A Statistical Framework for Expression-Based Molecular Classification in Cancer. J Royal Statistical Society (in press, 2002)