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Mary Helen Barcellos-Hoff
The ultimate goal of my research is to understand how multicellular processes are disrupted during the progression from normal growth to neoplasia. Fundamental control of individual cell function lies within the microenvironment, and entails cell-cell interactions and interplay between extracellular matrix, growth factors and hormones. Neoplasia requires the disruption of these extracellular controls concomitant with evolution of cellular mutations (Barcellos- Hoff, 1998b). Relatively little is known about aberrations in tissues architecture during the development of cancer or whether carcinogen exposure induces changes in multicellular organization in a manner that promotes neoplastic progression.
We study this question in mouse mammary gland following exposure to ionizing radiation, a known human carcinogen. We have used highly sensitive and precise cell biology techniques to map complex patterns of radiation-induced proteins in mouse mammary gland. We identified radiation-induced cytokines, in particular transforming growth factor-ß 1, as critical components of extracellular signaling pathways that mediate tissue response to radiation. The initial observation that TGF-ß is induced by ionizing radiation (Barcellos-Hoff, 1993) led to the development of methods to discriminate between latent and active TGF-ß in situ. We found that ionizing radiation leads to TGF-ß activation (Barcellos-Hoff et al., 1994), potentially by a novel mechanism of activation involving reactive oxygen (Barcellos-Hoff and Dix, 1996). These observations have direct relevance to the response of tissue to radiation (Ehrhart et al., 1997), inflammation (Chong et al., 1999) and in breast cancer (Reiss and Barcellos-Hoff, 1997).
Normal mammary gland biology is a necessary adjuvant of understanding the evolution of breast cancer. In collaboration with Dr. G. Shyamala, we are investigating the mechanisms and consequences of TGF-ß activation in normal mammary gland development. We have found that TGF-ß activation is highly restricted and regulated by ovarian steroid hormones, implicating TGF-ß as a pivotal control during mammary morphogenesis and function (Barcellos-Hoff et al., 2000).
Under the auspices of the Department of Energy Office of Biological and Environmental Research and in collaboration with Dr. Bahram Parvin of ICSD we are developing a bio-informatics framework of image acquisition, annotation and analysis to facilitate these studies. The goal is to create a database that registers localization information about multiple targets (e.g. growth factors, cell cycle determinants, cell adhesion, extracellular matrix, etc.) along with positional references and morphological features. Having the data stored in an integrated format will allow the development of tools to query the data for common patterns and multidimensional relationships. Used in conjunction with animal models of known radiation susceptibility, this innovative approach will enable construction of phenotype databases necessary to identify critical biological responses to low dose radiation exposure (Barcellos-Hoff, 1998a).
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