MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER
MMAC1/PTEN TUMOR SUPPRESSOR AND BREAST CANCER
批准号:
6514135
负责人:
GORDON B. MILLS
金额:
$26.24万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-09-01 至 2004-06-30
关键词:
biological signal transduction breast neoplasms cell cycle cell line enzyme activity gene expression genetic regulation genetic susceptibility laboratory mouse metastasis mutant neoplastic process neoplastic transformation phosphatidylinositol 3 kinase phosphorylation protein isoforms tissue /cell culture transforming growth factors tumor suppressor genes
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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财政年份:2010
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Modeling response to P13K Target Therapies
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资助金额:$56.25万
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财政年份:2010
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Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC)
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Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC)
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Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC)
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The Role of Aberrant Splicing of EVl1 in Ovarian Cancer Pathophysiology
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Targeting the PI3K Pathway in Ovarian Cancer
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海外基金