Breast cancer is a leading cause of cancer death among women. Current therapeutic strategies are mostly aimed at controlling malignant breast cancers. Although this strategy is helping patients by extending their lifespan, it does not provide long term benefits. I believe that there are alternative strategies that can be explored. If we can treat or control premalignant lesions so that they never progress to form malignant cancers, the patients can be maintained tumor-free. The bottleneck in accomplishing this goal is the almost complete lack of understanding of the mechanisms that regulate development and progression of precancerous lesions. My laboratory's long-term goal is to understand the molecular mechanisms that regulate development and progression of precancers.

While pathologists routinely use changes in tissue architecture to identify and categorize precancerous lesions (see Figure), the molecular mechanisms by which tissue architecture is lost is poorly understood. This is in part due to the use of cells cultured on plastic dishes to interrogate molecular mechanisms of cancer. Cells on plastic dishes do not recreate the normal 3-D organization of cells observed in tissues and hence are not suited to investigate how oncogenes disrupt organization of cells during genesis of carcinoma. We bridge this gap by the use of an organotypic, 3-D, cell culture method to recreate the epithelial organization seen in breast ducts and acinus in vivo. This method serves as an excellent platform to interrogate mechanisms that induce disruption of cell architecture observed in precancers. Using the 3-D culture method we have recently discovered that oncogenes, such as HER2/ErbB2, disrupt epithelial cell architecture by deregulating pathways that are involved in maintaining normal architectur/polarity of epithelial cells. Interestingly, the ability of ErbB2 to deregulate cells is independent of its ability to induce proliferation. Thus, we have uncovered a new arm of signaling used by oncogenes to disrupt cell and tissue architecture.

It is likely a deeper understanding of oncogenes that disrupt cell and tissue architecture will identify new targets for controlling early lesions. Our current efforts are focused on: 1) How do oncogenes target cell polarity pathways? 2) How do oncogenes interact with cell polarity pathways to disrupt tissue organization? 3) Do changes in cell polarity signaling pathways serve as predictive markers to stratify precancerous breast lesions for development of malignant disease? 4) Are pathways that control cell polarity novel targets for chemoprevention?