GENETIC AND HORMONAL FACTORS IN MAMMARY CARCINOGENESIS

乳腺癌发生中的遗传和激素因素

• 批准号: 3202283
• 负责人: SARASWATI SUKUMAR
• 金额: $ 16.09万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-14 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3202283
• 关键词: athymic mouse; breast neoplasms; epidermal growth factor; estrogens; gene deletion mutation; gene expression; gene mutation; hormone related neoplasm /cancer; juvenile animal; laboratory rat; metastasis; natural gene amplification; neoplasm /cancer genetics; newborn animals; oncogenes; ovariectomy; progesterone; transforming growth factors; tumor suppressor genes

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.

致癌物诱导的大鼠乳腺肿瘤模型系统，正在提供一种手段 了解癌症的分子机制及其作用 激素和生长因子在促进和进展中的作用 肿瘤。 在N-亚硝基-N‘-亚硝基乳腺中可检测到激活的ras癌基因。 -甲基尿素(NMU)治疗大鼠在注射后两周内 致癌物，强烈表明ras激活发生在 致癌的启动。仅ras癌基因的激活就是 不足以使乳腺细胞完全肿瘤性转化。 NMU治疗的大鼠的卵巢切除可以防止肿瘤的发展。后续 雌激素对无瘤大鼠乳腺的影响 肿瘤。因此，激素介导的乳腺增殖是 含突变ras的潜伏致癌乳腺细胞所必需的 癌基因表达它们的致瘤表型。此外，卵巢 荷尔蒙在乳腺肿瘤的发展过程中起着重要作用。作为对.的回应 卵巢切除后，70%的乳腺肿瘤消退(激素依赖)，而 30%的肿瘤继续生长(激素非依赖性)。在通过时， 同基因动物肿瘤变得侵袭，最后转移到 肺部。这很可能是因为在这一过程中，许多基因都处于失调状态 肿瘤发生克隆性扩张、局部组织侵袭和转移的过程。 为了与本RFA的目标保持一致，以进一步阐明 伴随荷尔蒙致癌的遗传事件，我们将研究 癌基因，如ras，neu和Prad-1，抑癌基因，如 作为P53、NF-1、WT-1、nm23和ST-3的基因，编码一种 基质细胞分泌的金属蛋白酶，因突变而失控， 大鼠乳腺肿瘤中的缺失、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 荷尔蒙和生长因子单独和组合的贡献， NMU启动的乳腺细胞的促进作用。我们希望 这项研究的结果将为理解 未来，异常基因产物和荷尔蒙之间的相互作用 在乳腺癌的促进和发展中起着至关重要的作用。