MICROENVIRONMENTS OF INVASION IN HUMAN BREAST TUMORS

We have developed state-of-the-art methods necessary to observe tumor cell invasion and intravasation directly in rat and mouse mammary tumors, correlate these cell behaviors with metastatic potential and connect these behaviors to the gene expression patterns seen in the migratory and invasive subpopulation of mammary tumor cells in the primary tumor. Furthermore, these methods can be used to characterize microenvironments that cause autocrine and paracrine-mediated cell migration resulting in the accumulation of cells around an initiating chemotactic signal, sometimes associated with blood vessels. This raises the exciting possibility that there exist self-propagating autocrine and paracrine loops that are tumor grade specific and that operate in the primary tumor, and possibly secondary and tertiary metastatic tumors, giving rise to systemic invasion and metastasis. Extension of this new technology to human breast tumors will allow us to explore the variety of stromal cells and microenvironments in this heterogeneous human tumor that are involved in invasion and metastasis, and determine if a cohort of gene expression changes exists as a common invasion signature that may have prognostic and therapeutic value. The specific aims of the proposal are: 1. Identify microenvironments involved in invasion in human breast tumors. 2. Determine gene expression profiles of invasive cells in human breast tumors.