GENETIC AND HORMONAL FACTORS IN MAMMARY CARCINOGENESIS

致癌物诱导的大鼠乳腺肿瘤模型系统，提供了一种手段 了解癌症的分子机制， 激素和生长因子在促进和发展 肿瘤形成 在N-nitroso-N'-N ' - 甲基脲（NMU）处理的大鼠在注射后两周内 致癌物质，强烈表明ras激活发生在 启动致癌作用。 ras癌基因的单独激活 不足以使乳腺细胞发生完全的肿瘤转化。 NMU处理的大鼠的卵巢切除术防止肿瘤发展。 后续 用雌激素治疗无瘤大鼠导致乳房出现 肿瘤的 因此，乳腺癌介导的乳腺增生是 对于含有突变ras的潜在致瘤性乳腺细胞是必需的 癌基因表达其致瘤表型。 此外，卵巢 激素在乳腺肿瘤的发展中起作用。 响应于 卵巢切除术后，70%的乳腺肿瘤消退（激素依赖性）， 30%的肿瘤继续生长（不依赖激素）。 在通过时， 在同源动物中，肿瘤变得具有侵袭性，并最终转移到 肺 很可能是许多基因在发育过程中失调， 癌细胞克隆性扩张、局部组织浸润和转移的过程。 为了与本RFA的目标保持一致， 伴随激素致癌的遗传事件，我们将研究 癌基因如ras、neu和PRAD-1，肿瘤抑制基因如 如p53、NF-1、WT-1和nm 23以及ST-3，编码一种 基质细胞分泌的金属蛋白酶，由于突变而失调， 缺失、扩增或易位。 使用 结合体内和细胞器培养系统，我们还将研究 激素和生长因子的作用，单独和组合， 促进NMU启动的乳腺细胞。 我们希望 本研究的结果将为理解 未来，异常基因产物和激素之间的相互作用， 在乳腺癌的促进和发展中起着至关重要的作用。

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.