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(American Journal of Pathology. 2007;170:1064-1076.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060031

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Andrea Sadlonova*, Shibani Mukherjee*, Damon B. Bowe{dagger}, Sandra R. Gault*, Nicole A. Dumas{ddagger}, Brian A. Van Tine*, Natalya Frolova*, Grier P. Page§, Danny R. Welch*, Lea Novak* and Andra R. Frost*

From the Departments of Pathology,* Medicine,{dagger} Pharmacology and Toxicology,{ddagger} and Biostatistics,§ The University of Alabama at Birmingham, Birmingham, Alabama

Stromal fibroblasts are important for normal breast homeostasis and regulation of epithelial growth; however, this regulatory function is altered during carcinogenesis. To study the role of fibroblasts in the development of breast cancer, fibroblasts derived from normal breast (NAFs) were incorporated into the MCF10AT xenograft model of progressive proliferative breast disease. The persistence of human NAFs in xenografts was established by intracellular labeling and tyramide-coupled fluorescent in situ hybridization. Overall, the number of MCF10AT epithelial structures was decreased, and the rate of epithelial cell apoptosis was increased in xenografts containing NAFs. However, these changes were primarily in low-grade epithelial structures, corresponding to normal or mildly hyperplastic ductal epithelium. The level and rate of apoptosis of high-grade epithelial structures, corresponding to in situ and invasive carcinoma, were not consistently altered by NAFs. In addition, there was variability in the growth-inhibitory capacity of NAFs derived from different individuals. NAFs induced changes in the morphology of high-grade MCF10AT structures and in xenograft stroma, including the composition of extracellular matrix, and increased angiogenesis and lymphocytic infiltration. These findings imply that NAFs can inhibit the growth of normal and hyperplastic epi-thelium but are less able to regulate the more transformed epithelial cells that arise during carcino-genesis.






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Copyright © 2007 by the American Society for Investigative Pathology.