Mammary neoplasia is the result of a complex interplay among genetic, environment, and host factors. The immune-endocrine system is believed to be central to this complex process. Similarly, tissue interactions in normal mammary gland are also important regulatory mechanisms in maintaining homeostasis. Aberrations in such mechanisms lead to progression of neoplastic disease. The present R01 is part of a coordinated program aimed at translating the basic concepts of immune- endocrine interactions during preneoplastic progression into an understanding of human breast cancer and to define gene expression heterogeneity in the context of preneoplastic potential. This R01 is designed to be the clinical test system of the principles underlying the concepts investigated in the other interactive R01s of this program. This R01 is focused on studies of gene expression that underlay the immune-endocrine-cytokine control of progression in clinical samples of human breast tissue from """"""""high risk"""""""" women, from """"""""benign"""""""" lesions, and from cancers. The identification and quantitation of cellular marker gene expression at different stages of breast carcinogenesis, tightly correlated with local histology, will clarify the functional relationships of these genes to tumor heterogeneity and progression. Heterogeneity in alterations of gene expression is likely to be detected more reliably than DNA alterations and, therefore to have potential value in tumor diagnosis and prognosis. Our primary objective is to identify profiles of gene expression in differing histologic types of proliferative disease and breast cancer, and in areas with differing patterns of growth and invasion. The chosen genes [PRL, PRL receptor, IL-2, IL-2R, TNFalpha, TGFalpha, TGFbeta and GM-CSF] are known to be altered in animal and human tumors at varying frequencies, but none are uniformly altered in all tumors. We plan to use immunohistochemistry, in situ hybridization and PCR based RNA quantitation method to localize the alterations of gene expression in tumor cells and in the cells of immune-endocrine importance in the context of tissue architecture. The results may suggest cause-effect relationships between deregulated gene expression and tumor progression and may form the basis for the analysis of those genes for the early detection of cancer or for the prediction of the biological behavior of a tumor so that proper therapeutic intervention can be devised. We expect that the use of a highly sensitive technique (PCR-based RNA quantitation) and exploration of heterogeneous regions within proliferative lesions and tumors should yield higher frequencies of aberration that can be tightly correlated with tissue histology and tumor progression, than do techniques that ignore tissue heterogeneity and architecture.
