THE IMPORTANCE OF THE MICROENVIRONMENT IN BREAST-CANCER PROGRESSION -RECAPITULATION OF MAMMARY TUMORIGENESIS USING A UNIQUE HUMAN MAMMARY EPITHELIAL-CELL MODEL AND A 3-DIMENSIONAL CULTURE ASSAY

The extracellular matrix (ECM) is a dominant regulator of tissue devel opment and homeostasis. ''Designer microenvironments'' in culture and in vivo model systems have shown that the ECM regulates growth, differ entiation, and apoptosis in murine and human mammary epithelial cells (MEG) through a hierarchy of transcriptional events involving the intr icate interplay between soluble and physical signaling pathways. Furth ermore, these studies have shown that these pathways direct and in tur n are influenced by the tissue structure. Tissue structure is directed by the cooperative interactions of the cell-cell and cell-ECM pathway s and can be modified by stromal factors. Not surprisingly then, loss of tissue structure and alterations in ECM components are associated w ith the appearance and dissemination of breast tumors, and malignancy is associated with perturbations in cell adhesion, changes in adhesion molecules, and a stromal reaction. Several lines of evidence now supp ort the contention that the pathogenesis of breast cancer is determine d (at least in part) by the dynamic interplay between the ductal epith elial cells, the microenvironment, and the tissue structure (acini). T hus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the stromal cells) with respe ct to tissue structure should be considered and studied. Towards this goal, we have established a unique human MEC model of tumorigenesis, w hich in concert with a three-dimensional assay, recapitulates many of the genetic and morphological changes observed in breast cancer in viv o. We are currently using this system to understand the role of the mi croenvironment and tissue structure in breast cancer progression.