Pak1 in Mammary Gland Development and Carcinogenesis

Pak1 在乳腺发育和癌变中的作用

• 批准号: 6739038
• 负责人: RAKESH KUMAR
• 金额: $ 27.45万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-18 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739038
• 关键词: angiogenesis; apoptosis; breast neoplasms; cell proliferation; chemical carcinogenesis; dimethylbenzanthracene; enzyme activity; enzyme induction /repression; genetic susceptibility; genetically modified animals; laboratory mouse; mammary gland; metastasis; neoplasm /cancer invasiveness; neoplastic process; protein kinase

DESCRIPTION: (Scanned from the applicant's abstract) The ability of the mammary gland to undergo tumorigenesis is influenced by its normal development, including reproductive events. Numerous epidemiological studies have suggested that systemic endocrine patterns and reproductive changes occurring in the human breast have important implications for breast cancer. The observation that the same endocrine events control mammary development and influence breast-cancer risk strengthens the hypothesis that mammary gland development and tumorigenesis are fundamentally linked. Understanding the mechanisms by which these events regulate breast cancer development will require a better understanding of the genes that control mammary cell proliferation and metastasis. Protein kinases are the largest class of genes known to regulate growth, differentiation, and development in eukaryotic organisms. We propose here to investigate the influence of p21-activated kinase (Paki), a serine/threonine kinase (with roles in motility, invasiveness, angio genesis, and cell survival), on the development of the normal mammary gland and alterations involved in early malignant and metastatic breast cancer. Our working hypotheses are that functional Pak1 pathway is required for normal mammary gland development and that deregulation of the Pak1 signaling pathway plays an essential role in the progression and maintenance of flu invasive phenotype in breast cancer by supporting cell survival and angiogenesis. The rationale for this proposal is based on observations recently made by the Principal Investigator that (i) expression of Pak1 controls motility, invasiveness and anchorage-independent growth of breast cancer cells; (ii) Pak 1 signaling regulates the expression of vascular endothelial growth factor and consequently its function; (iii) Pak1 activation supports cell survival by inactivating the proapoptotic protein Bad; and (v) conditional expression of a kinase-dead Paki in a transgenic mouse model leads to hypoplasia, retardation of ductal structures, and enhancement of intraductal stroma. These findings suggest that Pakl has a significant role in normal mammary development by controlling several essential functions, including cell motility and remodeling, angiogenesis, and cell survival. Thus dysfunctions in the Pakl pathwa3 may constitute an important step in breast cancer development. The Specific Aims of this proposal are to: (1) determine the influence of expression of dominant-negative Pakl in the mammary gland of transgenic mice; (2) determine the influence of constitutively active Paki on mammary gland biology in transgenic mice; (3) determine whether co-expression of Pakl can influence mammary gland tumorigenesis in HRG transgenic mice; and (4) determine the influence of Pak1 functions on the susceptibility. A unique aspect of our proposal is the use of recently developed Pak1 transgenic mice to gain novel insights about the role of Paki as critical signaling pathway in normal mammary gland development, and will also allow the Principal Investigator to validate the previous tissue culture findings in the pathophysiologically relevant experimental setting by using whole animals.

描述：（从申请人的摘要中扫描）乳腺的能力 腺体发生肿瘤受到其正常发育的影响， 包括生殖事件。大量流行病学研究表明 全身内分泌模式和生殖变化发生在 人类乳房对乳腺癌有重要影响。观察结果 相同的内分泌事件控制乳腺发育和影响 乳腺癌风险强化了乳腺发育的假说 和肿瘤的发生有着根本的联系。了解机制 这些事件调节乳腺癌的发展需要更好的研究 了解控制乳腺细胞增殖的基因 转移。蛋白激酶是已知调节的最大一类基因 真核生物的生长、分化和发育。我们建议 在此研究 p21 激活激酶 (Paki) 的影响，p21 激活激酶是一种 丝氨酸/苏氨酸激酶（在运动性、侵袭性、血管生成、 和细胞存活），对正常乳腺的发育和 涉及早期恶性和转移性乳腺癌的改变。 我们的工作假设是，功能性 Pak1 通路是正常细胞所必需的。 乳腺发育和 Pak1 信号通路的失调 在流感侵袭性的进展和维持中起着至关重要的作用 通过支持细胞存活和血管生成来改变乳腺癌的表型。 该提案的基本原理是基于最近的观察 首席研究员认为 (i) Pak1 的表达控制运动， 乳腺癌细胞的侵袭性和不依赖贴壁的生长； (二)朴 1信号调节血管内皮生长因子的表达 因此它的功能； (iii) Pak1 激活通过以下方式支持细胞存活 使促凋亡蛋白 Bad 失活； (v) 的条件表达式 转基因小鼠模型中激酶死亡的 Paki 导致发育不全、发育迟缓 导管结构和导管内基质的增强。这些发现 表明 Pakl 在正常乳腺发育中具有重要作用 控制多种基本功能，包括细胞运动和 重塑、血管生成和细胞存活。因此 Pakl 功能障碍 Pathwa3可能构成乳腺癌发展的重要一步。 该提案的具体目标是： (1) 确定 转基因小鼠乳腺中显性失活Pakl的表达； (2)确定组成性活性Paki对乳腺的影响 转基因小鼠的生物学； (3) 判断Pakl是否可以共表达 影响 HRG 转基因小鼠乳腺肿瘤的发生； (4) 确定 Pak1功能对敏感性的影响。我们的独特之处 提案是利用最近开发的 Pak1 转基因小鼠获得新的 关于 Paki 作为正常乳腺关键信号通路的作用的见解 腺体发育，也将允许首席研究员验证 先前的组织培养结果与病理生理学相关 使用整个动物进行实验设置。