Pak1 and Hormone Response in Breast Cancer Progression

描述（由申请人提供）：乳腺癌向更恶性行为发展的分子机制目前尚不完全清楚，据信与雌激素受体和生长因子信号之间的交叉对话解除以及与配体无关的内质网转激活有关。例如，p21活化激酶（Pak1）的激活是生长因子信号传导的主要靶点，它调节细胞的运动、侵袭性和存活，这些都是肿瘤发展和正常乳腺发育所必需的。尽管关于生长因子和Pak1生物学的信息显著增长，但新的Pak1靶点在乳腺癌中调节这些过程的机制仍然难以捉摸。我们的初步研究首次发现ER是Pak1的生理靶点，并且ER-Pak1通路的功能结局可能受到NRIF3和Ese1的磷酸化状态的密切影响，NRIF3和Ese1是两种功能相反的ER-相互作用Pak1底物。这一建议代表了PI的持续努力，以研究关键生理Pak1底物调节ER转激活并参与乳腺癌细胞致瘤表型发展的机制。

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.