MOLECULAR REGULATION OF BREAST CANCER METASTASIS
乳腺癌转移的分子调控
基本信息
- 批准号:6378082
- 负责人:
- 金额:$ 31.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-07-01 至 2003-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION: (Adapted from the investigator's abstract) We identified, cloned
and mapped a novel human gene, BRMS1 (Breast Metastasis Suppressor-1) which
suppresses metastasis when transfected into two unrelated human breast
carcinomas. Yet, tumorigenicity was not suppressed in the transfectants. These
characteristics define a metastasis-suppressor gene. The novel BRMS1 gene maps
to 11q13.1-q13.2, a chromosomal region commonly altered in late-stage,
metastatic breast carcinoma. Because of its relatively small size, nuclear
localization, presence of coiled-coil and leucine zipper motifs, we hypothesize
that BRMS1 is part of a multimeric protein complex involved in transcriptional
regulation. The objective of the current proposal is to determine the mechanism
by which BRMS1 suppresses breast carcinoma metastasis.
For Specific Aim 1, the underlying hypothesis is that precise disruption of the
BRMS1 protein will result in the inability to suppress the metastatic
phenotype. Following standard biochemical characterization (subcellular
localization, post-translational modification), BRMS1 mutants will be generated
by deletion and site-directed mutagenesis, transfected into metastatic human
breast carcinoma cells (which do not express endogenous BRMS1) and evaluated
for the mutants' effects o metastasis. Initial studies will disrupt the
putative nuclear localization signals to determine whether nuclear localization
is critical for BRMS1 function. Introduction of mutations to delete or modify
specific domains will then be done to assess which are critical. Subsequently,
missense mutations (e.g., alanine scan of critical amino acids) will introduce
more defined mutations. In a complementary study, BRMS1-interacting proteins
will be identified by co-precipitation and yeast two-hybrid analyses. Mutations
which result in disruption of protein-protein interactions and metastatic
potential will identify the critical amino acids responsible. Using this
combined approach, a structure-activity relationship can be developed for
BRMS1.
Specific Aim 2 will generate homozygous null brms1 mice. This aim will test
whether genetic loss of brms1 will result in increased metastasis by primary
murine mammary carcinomas. A conditional knockout approach using Cre-Lox will
be used in order to overcome the complications associated with a lethal
mutation. Introduction of Lox-flanked brms1 into the germline will be done,
followed by recombination using Cre under control of the MMTV and WAP promoters
(giving wisespread and mammary-tissue-specific deletion, respectively).
brms1-null mice will be bred to transgenic mice which routinely develop mammary
tumors and the incidence and frequency of metastasis determined. The hypothesis
is that mice lacking brms1 will develop more metastasis in more sites than mice
which still express brms1.
描述:(改编自研究者摘要)我们鉴定、克隆了
并绘制了一个新的人类基因BRMS 1(乳腺转移抑制因子-1),
当转染到两个无关的人乳腺癌细胞中时,
癌然而,在转染子中致瘤性没有被抑制。这些
特征定义了转移抑制基因。新的BRMS 1基因图谱
到11q13.1-q13.2,这是一个通常在晚期改变的染色体区域,
转移性乳腺癌由于其体积相对较小,
定位,卷曲螺旋和亮氨酸拉链基序的存在,我们假设
BRMS 1是多聚体蛋白复合物的一部分,
调控本提案的目的是确定机制
BRMS 1通过其抑制乳腺癌转移。
对于具体目标1,基本假设是,
BRMS 1蛋白将导致不能抑制转移性肿瘤细胞。
表型根据标准生化表征(亚细胞
定位、翻译后修饰),将产生BRMS 1突变体
通过缺失和定点诱变,转染到转移性人
乳腺癌细胞(其不表达内源性BRMS 1),并评估
突变体对转移的影响初步研究将破坏
推定的核定位信号,以确定核定位是否
对BRMS 1功能至关重要。引入突变以删除或修改
然后将对具体领域进行评估,以确定哪些领域是关键领域。随后,委员会注意到,
错义突变(例如,关键氨基酸的丙氨酸扫描)将引入
更明确的突变。在一项补充研究中,BRMS 1相互作用蛋白
将通过共沉淀和酵母双杂交分析来鉴定。突变
其导致蛋白质-蛋白质相互作用的破坏和转移
潜力将确定关键氨基酸负责。使用此
结合的方法,结构活性关系可以开发为
BRMS1.
特定目标2将产生纯合无效brms 1小鼠。这一目标将检验
BRMS 1基因缺失是否会导致原发性肝癌转移增加,
小鼠乳腺癌。使用Cre-Lox的条件性敲除方法将
用于克服与致命的
突变将Lox侧翼的brms 1引入种系,
随后在MMTV和WAP启动子的控制下使用Cre重组
(分别给出wisespread和乳腺组织特异性缺失)。
BRMS 1-null小鼠将被培育成转基因小鼠,
肿瘤和转移的发病率和频率确定。的假设
缺乏BRMS 1的小鼠将在更多部位发生更多转移
其仍然表达BRMS 1。
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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Danny R. Welch其他文献
Defining the biologic role of genes that regulate prostate cancer metastasis
定义调节前列腺癌转移的基因的生物学作用
- DOI:
- 发表时间:
2000 - 期刊:
- 影响因子:2.5
- 作者:
C. Rinker;Danny R. Welch;M. Sokoloff - 通讯作者:
M. Sokoloff
Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1
- DOI:
10.1007/s10585-020-10030-6 - 发表时间:
2020-02-22 - 期刊:
- 影响因子:3.200
- 作者:
Sitaram Harihar;Srijit Ray;Samyukta Narayanan;Anirudh Santhoshkumar;Thuc Ly;Danny R. Welch - 通讯作者:
Danny R. Welch
EV DNA from pancreatic cancer patient-derived cells harbors molecular, coding, non-coding signatures and mutational hotspots
胰腺癌患者来源细胞的循环肿瘤 DNA 携带有分子、编码、非编码特征和突变热点
- DOI:
10.1038/s42003-025-07567-1 - 发表时间:
2025-03-05 - 期刊:
- 影响因子:5.100
- 作者:
Appolinaire A. Olou;Wesley A. Tom;Gary Krzyzanowski;Chao Jiang;Dinesh S. Chandel;Nirmalee Fernando;Adrian W. Draney;Joel Destino;Danny R. Welch;M. Rohan Fernando - 通讯作者:
M. Rohan Fernando
The skeleton as a unique environment for breast cancer cells
- DOI:
10.1023/a:1022995403081 - 发表时间:
2003-05-01 - 期刊:
- 影响因子:3.200
- 作者:
Andrea M. Mastro;Carol V. Gay;Danny R. Welch - 通讯作者:
Danny R. Welch
Cancer metastasis : biologic basis and therapeutics
癌症转移:生物学基础和治疗学
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
D. Lyden;Danny R. Welch;B. Psaila - 通讯作者:
B. Psaila
Danny R. Welch的其他文献
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{{ truncateString('Danny R. Welch', 18)}}的其他基金
Cancer Research Training & Education Coordination CRTEC
癌症研究培训
- 批准号:
10671692 - 财政年份:2012
- 资助金额:
$ 31.46万 - 项目类别:
Cancer Research Training & Education Coordination CRTEC
癌症研究培训
- 批准号:
10493585 - 财政年份:2012
- 资助金额:
$ 31.46万 - 项目类别:
KISS1: Defining Mechanisms for Antimetastatic Therapy
KISS1:抗转移治疗的定义机制
- 批准号:
8545686 - 财政年份:2009
- 资助金额:
$ 31.46万 - 项目类别:
KISS1: Defining Mechanisms for Antimetastatic Therapy
KISS1:抗转移治疗的定义机制
- 批准号:
8101860 - 财政年份:2009
- 资助金额:
$ 31.46万 - 项目类别:
KISS1: Defining Mechanisms for Antimetastatic Therapy
KISS1:抗转移治疗的定义机制
- 批准号:
8332140 - 财政年份:2009
- 资助金额:
$ 31.46万 - 项目类别:
KISS1: Defining Mechanisms for Antimetastatic Therapy
KISS1:抗转移治疗的定义机制
- 批准号:
8676690 - 财政年份:2009
- 资助金额:
$ 31.46万 - 项目类别:
KISS1: Defining Mechanisms for Antimetastatic Therapy
KISS1:抗转移治疗的定义机制
- 批准号:
7737815 - 财政年份:2009
- 资助金额:
$ 31.46万 - 项目类别:
International Congresses - Metastasis Research Society
国际大会 - 转移研究协会
- 批准号:
6943021 - 财政年份:2004
- 资助金额:
$ 31.46万 - 项目类别:
International Congresses - Metastasis Research Society
国际大会 - 转移研究协会
- 批准号:
6829558 - 财政年份:2004
- 资助金额:
$ 31.46万 - 项目类别:
International Congresses - Metastasis Research Society
国际大会 - 转移研究协会
- 批准号:
7273681 - 财政年份:2004
- 资助金额:
$ 31.46万 - 项目类别:
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