MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER

描述：(改编自调查人员的摘要)背景：MMAC1 (也就是散发性乳腺组织中PTEN/TEP抑癌基因10q23的突变 癌症以及考登的乳腺癌易感综合征。MMAC1 已被证明是一种多功能磷酸酶，能够脱磷 蛋白质以及膜上肌醇环的3‘羟基 磷脂酰肌醇(Ptdlns)。这表明MMAC1针对的是信号 由磷脂酰肌醇3‘激酶(P13K)启动的级联反应。MMAC1基因的表达 在MMAC1突变的胶质瘤细胞中，生长速度和迁移减少 形成局灶性黏附复合体。MMAC1在乳腺癌中的作用 细胞还没有被探索过。 初步数据：我们的初步数据表明，MMAC1肿瘤 抑制基因通过P13K途径抑制信号而不影响 RAS/MAPK通路。LY294002对MMAC1的表达及P13K的抑制作用 在带有突变MMAC1的乳腺癌细胞中，MMAC1导致 增殖，这与增加的凋亡率和 阿尼基斯。 理论基础：拟议的研究将描述MMAC1 调控乳腺癌细胞中P13K信号级联反应及其功能 这种级联反应在乳腺癌的发生、发展和 转移瘤。对失活机制的理解(S) MMAC1抑癌基因在乳腺肿瘤发生中的作用 与发展、预后和治疗有关的重要新信息 散发性乳腺癌以及乳腺癌的遗传易感性 癌症。此外，MMAC1调节机制的特征 P13K级联反应可能为乳腺癌的治疗寻找新的靶点。 假设：MMAC1通过抑制P13K发挥肿瘤抑制作用 信令在多个级别上级联。具体目标#1：确定 MMAC1在乳腺癌细胞信号转导中的作用具体目标2： 确定MMAC1在乳腺癌发病机制中的功能作用。

DESCRIPTION: (adapted from the investigator's abstract) Background: The MMAC1 (a.k.a. PTEN/TEP tumor suppressor gene on 10q23 is mutated in sporadic breast cancer as well as in the Cowden's breast cancer predisposition syndrome. MMAC1 has been shown to be a multifunctional phosphatase capable of dephophorylating proteins as well as the 3' hydroxyl of the inositol ring of membrane phosphatidylinositols (Ptdlns). This suggests that MMAC1 targets the signaling cascade initiated by phosphatidyl inositol 3'kinase (P13K). Expression of MMAC1 in MMAC1 mutant glioma cells decreases growth rates and decreases migration and formation of focal adhesion complexes. The effects of MMAC1 on breast cancer cells has not been explored. Preliminary data: Our preliminary data indicates that the MMAC1 tumor suppressor gene inhibits signaling through the P13K pathway without affecting the RAS/MAPK pathway. Expression of MMAC1 or inhibition of P13K with LY294002 in breast cancer cells with mutant MMAC1 leads to a marked decrease in proliferation, which is associated with increased rates of apoptosis and anoikis. Rationale: The proposed studies will characterize the mechanisms by which MMAC1 regulates the P13K signaling cascade in breast cancer cells and the functional consequence of this cascade in breast cancer initiation, progression and metastases. An understanding of the mechanism(s) by which inactivation of the MMAC1 tumor suppressor contributes to breast tumorigenesis could provide important new information related to the development, prognosis and treatment of sporadic breast cancers as well as to genetic predisposition to breast cancer. Further, characterization of the mechanisms by which MMAC1 regulates the P13K cascade could identify new targets for therapy of breast cancer. Hypothesis: That MMAC1 acts as a tumor suppressor by inhibiting the P13K signaling cascade at multiple levels. Specific Aim #1: To determine the role of MMAC1 in signal transduction in breast cancer cells. Specific Aim #2: To determine the functional role of MMAC1 in breast cancer pathogenesis.