Carcinogen-induced rat mammary tumor model systems, are providing a means of understanding the molecular mechanisms underlying cancer and the role of hormones and growth factors in the promotion and progression of neoplasia. Activated ras oncogenes were detectable in mammary glands of N-nitroso-N'- -methylurea (NMU) treated rats within two weeks after injection of the carcinogen, strongly suggesting that ras activation occurs during initiation of carcinogenesis. Activation of ras oncogenes alone is insufficient for full neoplastic transformation of mammary gland cells. Ovariectomy of the NMU-treated rat prevents tumor development. Subsequent treatment of tumor-free rats with estrogen results in appearance of mammary tumors. Thus, hormone-mediated proliferation of the mammary gland is necessary for the latently tumorigenic mammary cells containing mutated ras oncogene to express their tumorigenic phenotype. In addition, ovarian hormones play a role in the progression of mammary tumors. In response to ovariectomy, 70% of the mammary tumors regress (hormone dependent), while 30% of the tumors continue to grow (hormone independent). Upon passage in syngeneic animals the tumors become invasive, and finally metastasize to the lungs. It is likely that scores of genes are dysregulated during the cancer process of clonal expansion, local tissue invasion and metastasis. In keeping with the aims of this RFA to shed additional light on the genetic events that accompany hormonal carcinogenesis, we will study whether oncogenes, such as ras, neu and PRAD-1, tumor suppressor genes such as the p53, NF-1, WT-1 and nm23 and ST-3, the gene that encodes a metalloproteinase secreted by stromal cells, are dysregulated by mutation, deletion, amplification, or translocation in rat mammary tumors. Using a combination of in vivo and organelle culture systems, we will also study the contribution of hormones and growth factors, singly and in combination, on the promotion of NMU-initiated mammary gland cells. We hope that the results of this study will provide the foundation to understanding in future, the interplay between aberrant gene products and hormones that play a crucial role in promotion and progression of breast cancer.
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