NATURAL SITE PREFERENCE IN CANCER BIOLOGY

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In the human breast, a spectrum of microscopic changes has been termed proliferative breast disease (PBD). Although hyperplastic lesions are observed in human breast, their role in disease progression is not understood. The progression of histopathological features of PBD has been correlated with increased risk for the development of invasive carcinoma. The most serve form of these lesions are precursors of cancer or simply markers of breasts likely to give rise to independent neoplastic lesions. The focal and microscopic lesions of PBD provide scant tissues for genetic or other biological analyses. A human cell line (MCF10A) originated from spontaneous immortalization of breast epithelial cells obtained from a patient with fibrocystic disease. MCF10A cells do not survive in vivo in Nude or Nude/Beige mice. However, T25 c-Ha-ras oncogene-transfected MCF10A cells (MCF10AneoT) form small nodules in Nude/Beige mice. However, T24 c-Ha-ras oncogene-transfected MCF10A cells (MCF10AneoT) form small nodules in Nude/Beige mice which persist for at least one year, eventually progress to atypical hyperplasia, and sporadically progress to carcinomas. MCF10AneoT appear to be stem cells capable of indefinite proliferation and with a wide range of differentiation from normal to atypical. By reestablishing cells in tissue culture from lesions representing different stages in in which persist for at least one year, eventually progress to atypical hyperplasia, and sporadically progress to carcinomas. MCF10AneoT appear to be stem cells capable of indefinite proliferation and different stages in progression of MCF10AneoT through atypical hyperplasia to carcinomas, we have been able to provide still snapshots of a dynamic process. These cell lines continue to progress when reimplanted in vivo in Nude/Beige mice but are sufficiently stable in vitro to provide the tools essential for he genetic analysis of progression. Thus, we are able to interrupt progression by placing cells in vitro and reinitiated progresses in vivo precipitate overt progression observed in xenografts. This unique model has great potential for analyzing genetic and epigenetic (i.eg., host- mediated) events central to progression from normal to atypical hyperplasia to carcinoma in the human breast. Our hypothesis is that sequential genetic alterations precipitate changes in human breast epithelial responses to normal homeostatic regulatory signals. We hypothesize that the progression of the MCF10AneoT series to malignant carcinomas is accompanied by changes in homeostatic responses similar to those which we have described in the mouse, i.e., that tumorigenic variants of MCF10AneoT will be stimulated by normal epithelium and be stromal-responsive but not stromal-dependent. Although Ha-ras is not frequently mutated in human breast cancer, we hypothesize that, in this model, the ras mutation mimics the effect of other, more common genetic perturbations and that subsequent alterations driving progression will be the same in this human breast model as in the natural disease. Therefore, analysis of genetic changes and homestatic responses with a series of increasingly aggressive lines will be vitally relevant for the understanding of early breast cancer progression. A multidisciplinary attack combining cell biology, molecular biology, and cytogenetics will be mounted to delineate genetic changes and changes in response to homeostatic growth regulatory factors which occur at each sequential step of progression to atypical hyperplasia, to carcinoma in situ, and to invasive carcinoma in the MCF10AenoT.TG xenograft model.