Although metastatic breast carcinoma is a major cause of death in W. Europe and N. America, to date there are few experimental systems for studying the metastatic behavior of this important disease. These proposed studies are to develop a model in nude mice to analyze the metastasis of estrogen- receptor negative human breast carcinomas, initially using established cell lines. The tumor cells will be injected into the mammary fat pads of female nude mice, an anatomatically appropriate site shown by us to support the growth and metastasis of neoplastic human breast cells. This model will be used to characterize different ER-negative human breast carcinomas for tumorigenicity and metastasis, and to isolate variant lines from metastases in different organs of the nude mice. Comparisons between the original cell lines and metastasis-selected variants, for in vitro and in vivo properties (growth rates in restricted serum conditions, colony-formation in 0.6%-1% agarose, adhesion to and invasion through extracellular matrices, growth properties in different organs of nude mice) will elucidate some of the intrinsic properties of human breast carcinomas that are critically associated with the metastatic phenotype. Transfection with a neomycin-resistance gene will generate uniquely labelled clones of human breast carcinoma cells. The remixed populations of several distinctly labelled clones will be used to analyze intra-tumor interactions in vitro (in different growth conditions) and in vivo (in mammary fat pads of mice). The studies will also address whether metastases in different organs originate from distinct """"""""organ-specific"""""""" populations, or from a common pool of metastatic cells capable of growth in many different organ environments. To explain in part the ability of some human breast carcinoma cells to proliferate as metastases in some organs, this proposal will investigate whether there is a heterogeneous response to the growth modulating effects of several defined growth factors (interferon, alpha, beta, and gamma, TGF alpha and beta, and MGF-I), using clonal populations, and correlate these in vitro findings with the metastatic phenotype. Also, to determine the influence of the normal organ environment on the growth of metastatic human breast carcinomas. The outcome of human breast carcinoma metastasis is dependent on the interactions of tumor cells with host factors. The results of the proposed studies should increase our understanding of this fatal disease.
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