SOM: Pathology and Laboratory Medicine
Center for Comparative Medicine
University of California, Davis
Dr. Borowsky is a Surgical Pathologist with expertise in Diagnostic Breast Pathology. His research training includes characterization of transgenic mouse models of prostate cancer and the molecular analysis of a fusion oncogene central to the pathogenesis of MALT lymphoma.
Breast Cancer Progression and DCIS
Among the population of neoplastic cells in human breast cancers, only a small minority - perhaps as few as one in 1000 - appear to be capable of forming new malignant tumors. Existing therapies are designed to kill as many cells within the tumor as possible, but it may be that these "cancer stem cells" are the critical target. This "cancer stem cell hypothesis" explains some of the clinical features unique to breast cancer progression (compared to other cancers, colon cancer for example). New technology has helped to identify these cells for the fist time, and opens the door to ask critical questions about what makes them tick.
We have developed a mouse model of mammary pre-cancer that precisely matches the properties of human breast pre-cancer (ductal carcinoma in situ-or DCIS). Several unexpected findings have lead to the hypothesis that we have isolated a functional pre-cancer stem tissue, harboring individual pre-cancer stem cells, and that these cells have a prescribed behavior that does not depend on additional influences. In other words, the pre-cancer stem cells we have discovered are pre-programmed to become cancers, at a specific time (latency) and with a specific behavior (metastatic or non-metastatic.) Can we identify and isolate these cells? What is their origin, and how are they programmed? Can they be re-programmed?
Identification of cancer stem cells in human breast cancers is a new technology. Finding these cells at the earliest possible time point in cancer or pre-cancer progression promises new insight on the earliest events leading to breast cancer. The model system we have developed is uniquely suited to finding these early cells. The combination of time-honored techniques of mouse mammary gland transplantation with new techniques for identifying cells with "stem cell" behavior is the innovative element. While there is some risk that these cells will not be accessible, preliminary evidence suggests that they can be isolated. This will provide evidence to support hypotheses of breast cancer initiation and progression mechanisms.
Genetically Engineered Mouse Models of Prostate Cancer
A number of prostate cancer models in mice have been generated. A recurring theme in these models is the frequent generation of large in situ lesions, but the rare occurrence of invasive adenocarcinoma. Understanding of the molecular pathways activated or disrupted in various genetically engineered mice and correlating this with the careful examination of the phenotypes that result, will lead to new hypotheses of oncogenesis. Sometimes these hypotheses can be tested using cross breeding of genetically engineered mice. Additional genetically engineered mice will be generated "from scratch" when necessary. The current interest of the laboratory is to further investigate a handful of potential tumor suppressor genes that are found to be down regulated in high throughput expression analysis studies. One example of this is Nes1, which appears to be down regulated by methylation early in Breast and Prostate Cancer. A strategy to create a tissue targeted (conditional) knockout of this gene is underway in the laboratory.
Translational Aspects of Breast and Prostate Cancer
With the recent explosion of gene expression profiles, including work at the UC Davis Cancer Center, there is a growing need for validation and translation of these data into sorting out clinically and biologically relevant findings. New ways of employing these findings in clinical practice are necessary. Traditionally Northern blot analysis is used to validate microarray findings. However, this requires relatively pure cell populations which are uncommon in human disease. The Borowsky lab uses the Laser Capture Microdissector (LCM) instrument coupled with real time quantitative PCR to evaluate gene expression levels in specific cell populations in human tissues and tumors.