MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER

描述：（改编自研究者摘要）背景：MMAC 1 （又名：散发性乳腺癌10 q23区PTEN/TEP抑癌基因突变的研究 癌症以及考登乳腺癌易感综合征。MMAC1 已显示是一种多功能磷酸酶，能够使 蛋白质以及膜的肌醇环的3'羟基 磷脂酰肌醇（Ptdlns）。这表明MMAC 1靶向信号传导， 由磷脂酰肌醇3 '激酶（P13 K）启动的级联反应。MMAC 1的表达 在MMAC 1突变胶质瘤细胞中，生长速率降低，迁移减少， 形成粘着斑复合物。MMAC 1对乳腺癌的作用 细胞尚未被探索。 初步数据：我们的初步数据表明，MMAC 1肿瘤 抑制基因通过P13 K途径抑制信号传导，而不影响 RAS/MAPK通路。用LY 294002表达MMAC 1或抑制P13 K 在乳腺癌细胞中，突变MMAC 1导致 增殖，这与凋亡率增加有关， 失巢。 依据：拟定研究将描述MMAC 1 调节乳腺癌细胞中的P13 K信号级联， 这种级联反应在乳腺癌发生、进展和 转移了解灭活的机制， MMAC 1肿瘤抑制因子有助于乳腺肿瘤发生， 与发展、预后和治疗相关的重要新信息 散发性乳腺癌以及乳腺癌的遗传易感性 癌此外，MMAC 1调节的机制的表征 P13 K级联反应可以为乳腺癌的治疗确定新的靶点。 假设：MMAC 1通过抑制P13 K发挥肿瘤抑制因子的作用 多层次的信号级联。具体目标#1：确定 MMAC 1在乳腺癌细胞信号转导中的作用具体目标#2： 确定MMAC 1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.