Malignant Transformation in Breast Epithelium

Institution: Stanford University
Investigator(s): Heinz Furthmayr, M.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1SB-0004 Award: $54,000
Award Type: Sabbatical Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1995)
Several mechanisms are involved in the invasion of tissues by, and metastatic spread, of tumor cells. Among these are loss of differentiation, differences in communication between cells and with the extracellular environment, activation of proteolytic enzymes and changes in intracellular transfer of signals. The abnormal cell behavior of invasive tumor cells is not the result of a single change but rather likely is caused by several interdependent events. The research during this sabbatical period will focus on mechanisms breast cancer cells use to communicate with each other and to sense their environment.

The extracellular matrix plays a critical role in differentiation in the breast gland and in growth regulation, motility and death of the cells. In response to signals from the extracellular matrix, cells change shape as a result of precisely regulated rearrangements of proteins within the cell. These involve modifying enzymes, which act upon internal cytoskeletal proteins and regulate protein-protein interactions. It is believed that such signals are received by delicate and transiently formed extensions, called pseudopodia, which specifically recognize the extracellular matrix and transmit information for processing. These cellular structures are critical for cell movement and hence, for invasion of tissues and the ability of tumor cells to metastasize. Fluorescent derivatives of several relevant proteins will be prepared for introduction into mammary cells by microinjection and other methods. These cells will then be studied by time-lapse video and fluorescence microscopy.

The ultimate goal of this research program is the ability to interfere with the invasive property of breast cancer cells.

Final Report (1996)
A fundamental issue in biology relates to molecular mechanisms regulating differentiation. In a complex tissue such as the mammary gland, this is determined by multiple factors including stimulation by growth factors, hormones, intercellular communication and interactions with the extracellular matrix. Thus, multiple stimuli influence cellular responses during breast development, during pregnancy, during lactation, to simultaneously arrest cell proliferation and to establish functions appropriate for the gland, such as the production of milk. The converse is also true, since abnormal growth in breast cancer is correlated with less differentiation. Cancer and metastatic cells become incapable of maintaining or establishing a normal, functionally intact and hormonally responsive tissue architecture.

It is the cell surface of mammary epithelial cells that mediates the interplay with the extracellular environment. Similar to other cells, the cell membrane and underlying structures exhibit dynamic changes that are characterized by protrusion of various processes. It is believed that these dynamic and specialized protrusions mediate many of the recognition and signaling functions that allow cells to move, to establish contact with other cells and to ultimately form a functionally normal gland. Three members of a small family of proteins are found in these protrusions in many different cell types. These proteins, called moesin, ezrin and radixin, link membrane proteins (so called receptors) that exist on the surface of cells, to intracellular proteins.

The goal of the research was to gain experience with an appropriate experimental system to determine how such protrusions accomplish their tasks in breast cells. Mouse breast tissue and mouse and human cells in tissue culture were studied and it was found that at least two of the proteins (moesin, ezrin) are made by those cells. This knowledge is significant and will help to specifically address questions related to the behavior of breast cancer cells in response to altered environmental factors.