Pak1 and Hormone Response in Breast Cancer Progression

乳腺癌进展中的 Pak1 和激素反应

• 批准号: 7414079
• 负责人: Rakesh Kumar
• 金额: $ 24.48万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414079
• 关键词: Address; Affect; Behavior; Biology; Breast Cancer Cell; Breast Carcinoma; Cancer Biology; Cells; Characteristics; Cyclic AMP-Dependent Protein Kinases; Cyclins; Data; Development; Diagnosis; Epithelial; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Family member; Glutamic Acid; Growth; Growth Factor; Hormones; Human; Hyperplasia; In Vitro; Invasive; Knowledge; Laboratories; Ligands; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Molecular; Molecular Target; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Principal Investigator; Process; Regulation; Regulatory Pathway; Research; Role; Serine; Signal Transduction; Site; Specimen; Tamoxifen; Time; Transactivation; Transgenic Model; Transgenic Organisms; United States; Woman; Work; base; cell motility; design; follow-up; functional outcomes; in vivo; innovation; insight; malignant breast neoplasm; member; mouse model; mutant; neoplastic cell; novel; outcome forecast; p21 activated kinase; prevent; response; therapeutic target; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The molecular mechanisms underlying the progression of breast cancer to more malignant behavior are not completely understood at the present time and are believed to involve deregulation of cross-talk between estrogen receptor and growth factor signaling, and also ligand-independent ER transactivation. For example, activation of p21-activated kinase (Pak1), a major target of growth factor signaling, regulates cell motility, invasiveness and survival, all of which are required for both tumor development and also normal mammary gland development. Despite the remarkable growth of information about growth factors and Pak1 biology, the mechanism by which novel Pak1 targets regulate these processes in breast cancer remains elusive. Our preliminary studies have discovered for the first time that ER is a physiological target of Pak1 and that the functional outcome of ER-Pak1 pathway may be closely influenced by the phosphorylation status of NRIF3 and Ese1, two novel ER-interacting Pak1 substrates with opposing functions. This proposal represents a continuing effort of the PI to investigate the mechanism by which critical physiologic Pak1 substrates modulate ER transactivation and participates in the development of tumorigenic phenotypes in breast cancer cells. Our working hypothesis is that "deregulation of Pak1 activity stimulates the ER pathway, and consequently, contributes to an enhanced hormone response, hormone-independence, and tumorigenesis of breast tumor cells; these phenotypic effects of ER might be controlled by the modulation of actions of NRIF3 and Ese1, two novel ER-interacting Pak1 substrates that modulate the ER transactivation in a stimulatory or inhibitory manner, respectively." This proposal will clarify the role of growth factor signaling in hormone-independence and breast cancer progression by defining the mechanistic significance of specific downstream physiologic targets of Pak1 such as ER, NRIF3 and Ese1, and to establish the role of ER-Ser305 and Ser118 activation in the normal mammary gland development and tumorigenesis. To address these hypotheses, our Specific Aims are to determine: (1 )The functional significance of Pak1-ER pathway in the mammary gland development and tumorigenesis; (2) The influence of Pak1 regulation of NRIF3-Ser28 in the action of ER and associated phenotypic changes; (3) The role of Ese1 and its phosphorylation by Pak1 in modifying ER functions and breast cancer biology; (4)The expression characteristics and significance of Pak1, ER, and Ese1 during multi-step pathogenesis of breast carcinoma and in-patients with invasive breast cancer. An innovative aspect of our proposal is the use of novel in vitro, in vivo and transgenic models, as well as human breast tumors with follow-up data to gain new insights about the mechanistic and functional significance of Pak1-ER pathway by NRIF3 and Ese1 in breast cancer cells. These studies will uniquely define the mechanisms through which ER and its upstream Pak1 kinase and downstream coregulators NRIF3 and Ese1 modulate hormone action. This research is significant in that the knowledge gained from this research will enhance our understanding of the critical regulatory pathways with established roles in breast cancer progression.

描述（由申请人提供）：目前尚未完全了解乳腺癌进展到更恶性行为的分子机制，并且据信涉及雌激素受体受体和生长因子信号传导之间的串扰，也涉及不依赖配体的ER反式激活。例如，p21激活激酶（PAK1）的激活是生长因子信号传导的主要目标，调节细胞运动，侵入性和存活，所有这些都是肿瘤发育以及正常的乳腺发育所必需的。尽管有关生长因子和PAK1生物学的信息显着增长，但新型PAK1靶向调节这些过程在乳腺癌中的机制仍然难以捉摸。我们的初步研究首次发现ER是PAK1的生理靶标，并且ER-PAK1途径的功能结果可能受到NRIF3和ESE1的磷酸化状态的紧密影响，这是两个具有相反功能的新型ER互联PAK1底物。该提案代表了PI的持续努力，以研究关键生理PAK1底物调节ER反式激活并参与乳腺癌细胞中肿瘤性表型的发展的机制。 Our working hypothesis is that "deregulation of Pak1 activity stimulates the ER pathway, and consequently, contributes to an enhanced hormone response, hormone-independence, and tumorigenesis of breast tumor cells; these phenotypic effects of ER might be controlled by the modulation of actions of NRIF3 and Ese1, two novel ER-interacting Pak1 substrates that modulate the ER transactivation in a stimulatory or分别抑制方式。”该建议将通过定义PAK1的特定下游生理靶标（例如ER，NRIF3和ESE1）的机理意义，并确定正常乳腺发育和肿瘤的正常乳腺发育和肿瘤的作用，从而阐明生长因子信号传导在激素独立性和乳腺癌进展中的作用。 为了解决这些假设，我们的具体目的是确定：（1）PAK1-ER途径在乳腺发育和肿瘤发生中的功能意义； （2）NRIF3-SER28对ER和相关表型变化的作用的PAK1调节的影响； （3）ESE1及其通过PAK1磷酸化的作用在修饰ER功能和乳腺癌生物学中的作用； （4）在乳腺癌和侵入性乳腺癌患者的多步发病机理中，PAK1，ER和ESE1的表达特征和意义。我们提案的一个创新方面是使用新型体外，体内和转基因模型以及具有后续数据的人类乳腺肿瘤，以获得有关NRIF3和ESE 1在乳腺癌细胞中PAK1-ER途径的机械和功能意义的新见解。这些研究将唯一地定义ER及其上游PAK1激酶和下游核心测量剂NRIF3和ESE1调节激素作用的机制。这项研究很重要，因为从这项研究中获得的知识将增强我们对乳腺癌进展中既定作用的关键监管途径的理解。