ACTIVATION-SPECIFIC C-ERBB-2 DETECTION IN BREAST CANCER
乳腺癌中的激活特异性 C-ERBB-2 检测
基本信息
- 批准号:2102849
- 负责人:
- 金额:$ 8.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-03-07 至 1997-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Approximately 50% of patients presenting with breast cancer have lymph
node-negative tumors. Although the overall prognosis for such patients
is substantially better than for those with positive node. 30% will
still succumb to metastatic disease. Experience with node-positive
disease suggests that this false-negative patient cohort may derive
significant survival benefit form adjuvant systemic therapy.
Expression of the c-erbB-2 (neu, HER-2) receptor has been proposed as one
criterion for predicting the natural history of human breast cancer, but
the predictivity of this receptor in early-stage disease remains
uncertain. My previous work established that c-erbB-2 receptors exist
in two interconvertible forms- an activated 175kDa(p(175) tyrosine-
phosphorylated form, and an inactive 185kDa(p185) tyrosine-
dephosphorylated form. This work led to the characterization of p175
expression in human tumor cells using activation-specific antibodies
created by immunizing animals with synthetic phosphopeptides duplicating
the sequence of a major c-erbB-2 autophosphorylation site. The present
proposal aims to clarify the pathogenetic and prognostic significance of
the c-erb-B-2 phenotype in human breast cancer by exploiting this novel
technology. The project has three objectives:
The first objective is to determine the signalling significance of
individual c-ebb-2 receptor autophosphorylation sites by generating
polyclonal antisera to the relevant phospho- and dephosphopeptides:
The second objective is to raise activation- and inactivation-specific
monoclonal antibodies to phosphopeptide sequences identifying different
c-ebb-2 receptor activation states.
The third objective is to use these activation-specific monoclonal
antibodies to define expression of p175 and p185 in pre-invasive,
invasive and metastatic breast tumors, and to correlate presence of these
receptor isoforms with expression of the c-ebb-2 ligand (heregulin) at
the mRNA and protein levels.
These clinicopathologic correlations will establish the feasibility of
a prospective randomized study of adjuvant systemic treatment based on
expression of p175, p185 and heregulin in node-negative breast tumors.
This goal is both achievable and timely given the advent of activation-
state-specific phosphoprotein immunodetection (APHID) technology, the
track record of the CRC Breast Group in the characterization of human
breast tumors in vivo, and the recent amalgamation of Charing Cross
Medical School with Imperial College of Science and Technology. The most
important factor favoring success in this project, however, is that the
CRC Laboratories provided unlimited access to a bank of 4000 frozen
breast cancer specimens, together with computerized databases supplying
all details of breast cancer clinical presentation, disease stage,
therapeutic response and survival outcome.
大约50%的乳腺癌患者有淋巴结转移。
淋巴结阴性肿瘤 尽管这些患者的总体预后
基本上优于具有正节点的那些。 30%将
仍然死于转移性疾病。 关于node-positive
疾病表明,这种假阴性患者队列可能源于
从辅助全身治疗中获得显著生存益处。
c-erbB-2(neu,HER-2)受体的表达已被提出作为一种
预测人类乳腺癌自然史的标准,但
这种受体在早期疾病中的预测性仍然存在
不确定 我之前的工作证实了c-erbB-2受体的存在
以两种可相互转化的形式存在-活化的175 kDa(p(175)酪氨酸-
磷酸化形式,和无活性的185 kDa(p185)酪氨酸-
去磷酸化形式。 这项工作导致了p175的特征
使用活化特异性抗体在人肿瘤细胞中的表达
通过用合成的磷酸肽复制免疫动物
c-erbB-2主要自磷酸化位点的序列。 本
该提案旨在阐明
人乳腺癌c-er B-B-2表型的研究
技术. 该项目有三个目标:
第一个目标是确定
单个c-ebb-2受体自身磷酸化位点,
相关磷酸肽和脱磷酸肽的多克隆抗血清:
第二个目标是提高激活和失活特异性
磷酸肽序列的单克隆抗体鉴定不同的
c-ebb-2受体激活状态。
第三个目的是使用这些激活特异性单克隆抗体,
确定p175和p185在侵袭前,
侵袭性和转移性乳腺肿瘤,并将这些肿瘤的存在与
受体亚型与c-ebb-2配体(heregulin)的表达,
mRNA和蛋白质水平。
这些临床病理学相关性将确立
一项基于以下因素的辅助全身治疗的前瞻性随机研究:
p175、p185和heregulin在淋巴结阴性乳腺肿瘤中的表达
这一目标是可以实现的,也是及时的,因为激活的到来-
状态特异性磷蛋白免疫检测(APHID)技术,
CRC乳腺组在人类
乳腺肿瘤在体内,和最近的合并查林十字
医学院与帝国理工学院。 最
然而,有利于该项目成功的重要因素是,
CRC实验室提供了无限制的访问一个银行的4000冻结
乳腺癌标本,连同计算机化的数据库,
乳腺癌临床表现的所有细节,疾病阶段,
治疗反应和生存结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RICHARD J EPSTEIN的其他文献
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{{ truncateString('RICHARD J EPSTEIN', 18)}}的其他基金
ACTIVATION-SPECIFIC C-ERBB-2 DETECTION IN BREAST CANCER
乳腺癌中的激活特异性 C-ERBB-2 检测
- 批准号:
2102850 - 财政年份:1994
- 资助金额:
$ 8.59万 - 项目类别:
ACTIVATION-SPECIFIC C-ERBB-2 DETECTION IN BREAST CANCER
乳腺癌中的激活特异性 C-ERBB-2 检测
- 批准号:
2102851 - 财政年份:1994
- 资助金额:
$ 8.59万 - 项目类别:
ACTIVATION SPECIFIC C ERBB 2 DETECTION IN BREAST CANCER
乳腺癌中 C ERBB 2 的激活特异性检测
- 批准号:
3460472 - 财政年份:1992
- 资助金额:
$ 8.59万 - 项目类别:
ACTIVATION SPECIFIC C ERBB 2 DETECTION IN BREAST CANCER
乳腺癌中 C ERBB 2 的激活特异性检测
- 批准号:
3460471 - 财政年份:1992
- 资助金额:
$ 8.59万 - 项目类别: