MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER

描述：（改编自研究者的摘要）背景：MMAC1 （又名 10q23 上的 PTEN/TEP 肿瘤抑制基因在散发性乳腺癌中发生突变 癌症以及考登乳腺癌易感综合症。 MMAC1 已被证明是一种能够去磷酸化的多功能磷酸酶 蛋白质以及膜肌醇环的3'羟基 磷脂酰肌醇（Ptdlns）。这表明 MMAC1 的目标是信号传导 由磷脂酰肌醇 3' 激酶 (P13K) 引发的级联反应。 MMAC1的表达 MMAC1 突变神经胶质瘤细胞中的 MMAC1 会降低生长速度并减少迁移和 粘着斑复合物的形成。 MMAC1对乳腺癌的影响 细胞尚未被探索。 初步数据：我们的初步数据表明 MMAC1 肿瘤 抑制基因通过 P13K 途径抑制信号传导而不影响 RAS/MAPK 通路。 LY294002 表达 MMAC1 或抑制 P13K 在具有突变 MMAC1 的乳腺癌细胞中，导致 增殖，这与细胞凋亡率增加有关 失巢。 理由：拟议的研究将描述 MMAC1 的机制 调节乳腺癌细胞中的 P13K 信号级联和功能 这种级联反应在乳腺癌发生、进展和 转移。了解失活机制 MMAC1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倾向 癌症。此外，MMAC1 调节机制的表征 P13K级联可以确定乳腺癌治疗的新靶点。 假设：MMAC1 通过抑制 P13K 发挥肿瘤抑制因子的作用 多个级别的信号级联。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.