Roles of class 1A PI3K isoforms in mammary epithelium function and breast cancer

描述（由申请人提供）：IA类磷脂酰肌醇3-激酶（PI 3 K）被生长因子受体酪氨酸激酶（RTK）和Ras激活，产生主要的细胞内脂质信号，磷脂酰肌醇3，4，5-三磷酸（PIP 3），这是多种细胞过程（包括存活、增殖和分化）所必需的。肿瘤抑制因子PTEN，一种脂质磷酸酶，使PIP 3去磷酸化，因此抵消PI 3 Ks的作用。IA类PI 3 K信号通路通过直接或间接诱变事件的组成性激活是人类乳腺癌中最常见的事件之一。因此，1A类PI 3 K是乳腺癌治疗干预的有吸引力的靶标。在哺乳动物中，有两个1A类PI 3 K催化亚型，p110？P110？其在上皮组织/器官等部位广泛表达。尽管它们在分子结构和酶活性上相似，但最近的研究表明这两种异构体在细胞信号传导和致癌转化中具有不同的功能。然而，我们对每种类型的PI 3 K的具体功能的了解非常有限。所有IA类PI 3 K对经典PI 3 K抑制剂渥曼青霉素和LY 294002表现出相同的敏感性。缺乏p110的小鼠？还是p110是早期胚胎致死的，这排除了进一步描述其特定功能。我们最近产生了p110基因的条件性敲除动物？P110？通过Cre/loxP重组系统重组1A类PI 3 Ks基因，以促进1A类PI 3 Ks的研究。在这个应用程序中，我们要测试我们的假设，p110？P110？在乳腺上皮功能和肿瘤发生中具有独特的生物学作用。这一假设导致我们提出的预测，在细胞培养和动物模型中进行测试。具体目标如下。1.为了验证p110？P110？在小鼠乳腺上皮细胞（MMECs）的信号转导和细胞增殖中具有独特的作用。2.为了验证p110？P110？在乳腺发育中有不同的作用。3.为了验证p110？P110？在由致癌Her 2/Neu驱动的乳腺肿瘤发生中具有独特的功能。这些研究将促进我们对PI 3 K亚型功能的理解，并为开发有效，特异性和毒性较小的PI 3 K抑制剂用于癌症治疗提供关键信息。公共卫生相关性：IA类PI 3 K信号通路在高百分比的人类癌症（包括乳腺癌、脑癌和结肠癌）中被过度激活，并且也非常适合于药物干预。然而，由于PI 3 K活性参与多种基本生理功能，因此其抑制可能具有毒性副作用的风险相当大。从这项研究中获得的信息不仅将为我们提供PI 3 K亚型在正常乳腺组织功能和肿瘤发病机制中的全面知识，而且还将帮助我们评估关键药物靶点，以促进开发更特异性和毒性更低的乳腺癌治疗药物。

DESCRIPTION (provided by applicant): Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptor tyrosine kinases (RTKs) and Ras to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), essential for multiple cellular processes, including survival, proliferation and differentiation. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3 and therefore counteracts the action of PI3Ks. Constitutive activation of the class IA PI3K signaling pathway via direct or indirect mutagenic events is amongst the most frequent events in human breast cancer. Thus, class 1A PI3Ks are attractive targets for therapeutic intervention in breast cancer. In mammals, there are two class 1A PI3K catalytic isoforms, p110? and p110?, which are ubiquitously expressed in epithelial tissues/organs, among other sites. Despite their similarity in molecular structure and enzymatic activity, recent studies suggest that the two isoforms have distinct functions in cell signaling and oncogenic transformation. However, we have very limited understanding of the specific functions for each type of PI3K. All class IA PI3Ks display the same sensitivity to the classical PI3K inhibitors wortmannin and LY294002. Mice lacking p110? or p110? are early embryonic lethal, which precluded further delineation of their specific functions. We recently generated conditional knockout animals for the p110? and p110? genes via the Cre/loxP recombination system to facilitate the study of class 1A PI3Ks. In this application, we want to test our hypothesis that p110? and p110? have distinct biological roles in mammary epithelium function and tumorigenesis. This hypothesis leads to predictions that we propose to test in cell culture and animal models. The Specific Aims are as follows. 1. To test the prediction that p110? and p110? have distinct roles in signal transduction and cell proliferation in mouse mammary epithelial cells (MMECs). 2. To test the prediction that p110? and p110? have distinct roles in mammary gland development. 3. To test the prediction that p110? and p110? have distinct functions in breast tumorigenesis driven by oncogenic Her2/Neu. These studies will advance our understanding of the functions of PI3K isoforms and provide information critical to developing effective, specific and less toxic PI3K inhibitors for cancer treatment. PUBLIC HEALTH RELEVANCE: The Class IA PI3K signaling pathway is hyper-activated in a high percentage of human cancers, including breast, brain and colon cancers, and is also highly suited for pharmacologic intervention. However, because PI3K activity is involved in multiple fundamental physiological functions, there is a considerable risk that its inhibition may have toxic side effects. The information derived from this study will not only provide us with comprehensive knowledge of PI3K isoforms in normal breast tissue function and tumor pathogenesis, but will also help us to evaluate critical drug targets to facilitate the development of more specific and less toxic drugs for breast cancer treatment.