BryanWelm's PubMed Literature Search
Research in my laboratory is focused on understanding both the normal processes regulating cell fate determination in the breast, and the relationship between cellular differentiation and cancer. Pathological states of the breast, such as pre-neoplastic lesions and carcinomas, retain aspects of cellular heterogeneity similar to that observed in the normal breast. This cellular heterogeneity is observed by both histological analyses of cancer tissue, and through assays where different cancer cell populations are enriched and transplanted into mice. Based on the regenerative capacity of enriched cell populations, it is clear that in breast cancer a cellular hierarchy exists. Studies using FACS sorted tumor cells have shown that a limited cell population, distinguished by the expression of the cell surface proteins CD44 and CD24, contains the full regenerative potential of the tumor and can reproduce its cellular heterogeneity upon transplantation. These data suggest that tumors are derived from a multi-potential tumor-initiating cell, or cancer stem cell, that controls the growth and cellular homeostasis of the cancer.
Breast cancer can be categorized into distinct subtypes based on the pattern of genes expressed by the tumor. These gene expression signatures correlate with clinical outcome and provide insight into the complex molecular pathways driving the disease. The question remains whether specific molecular pathways establish the subtype or whether different cell types within the mammary hierarchy become transformed and give rise to each tumor subtype. These questions are difficult to address using existing models of breast cancer since cell lines may not retain the same cell population as the original tumor, and transgenic mouse models of breast cancer utilize promoters that are preferentially expressed in more differentiated cells. Therefore, my laboratory is developing new model systems that more appropriately mimic the cellular heterogeneity observed in breast cancer. Using these breast cancer models we are performing the following projects:
Breast cancer is a disease with significant diversity in histology, cellular composition and clinical outcome. This diversity may result from either specific genetic mutations or transformation of different cell populations. We are performing experiments to determine whether specific oncogenic pathways targeted to different mammary epithelial cell populations can affect the cellular composition and pathology of tumors.
The heterogeneous nature of breast cancer may reflect both its cellular origin and activation of specific signaling pathways. The complex etiology of breast cancer is not appropriately reproduced with established cell lines, making them of limited use in drug discovery screens. Therefore, we are developing a chemical library screen using primary tumor cells that embody the diversity of the signaling pathways activated, and the cellular variation of the original tumor. Primary tumor cells, representing both basal and luminal cancer subtypes, have been generated using an oncogene-induced mouse model of breast cancer. Tumor cells are pre-screened by both gene expression profiling and histology to identify the cancer subtype that they represent. The tumor cells representing specific subtypes are grown as 3D organoids within a laminin-rich extracellular matrix and screened using different chemical libraries. We anticipate that this screening process should increase the number of candidate compounds that succeed in validation studies due to the close relationship between the cells in the assay and the originating tumor.