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The Role of FOXCI in Basal-like Breast Cancer

FOXCI 在基底样乳腺癌中的作用

基本信息

批准号：
10331776
负责人：
Xiaojiang Cui
金额：
$ 40.73万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-14 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331776
关键词：
Affect Antiestrogen Therapy Area Automobile Driving BRCA1 Mutation BRCA1 Protein BRCA1 gene BRCA2 gene Behavior Biochemical Biological Biological Factors Biological Markers Biological Response Modifier Therapy Biology Blood Brain Breast Breast Cancer Cell Breast Cancer Genetics Breast Cancer Treatment Breast Epithelial Cells Breast cancer metastasis CXCL1 gene Cell Proliferation Cell model Cell physiology Cells Characteristics Classification Clinical Data Development EGF gene ERBB2 gene Endothelial Cells Erinaceidae Estrogen Receptors FOXC1 gene Fibroblasts Foundations Funding Gene Expression Genes Goals Histopathologic Grade Human In Vitro Inflammatory Injections Lead Light Lung Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic malignant neoplasm to brain Modality Molecular Mus Myoepithelial cell Neoplasm Metastasis Organ Outcome Phenotype Play Population Process Progesterone Receptors Prognosis Proteins Reactive Oxygen Species Reporting Resistance Reverse Transcriptase Polymerase Chain Reaction Risk Role Signal Pathway Signal Transduction Structure of parenchyma of lung Subgroup Systemic Therapy Tail Testing Tissues Veins Xenograft Model angiogenesis base breast cancer progression cell motility chemokine chemotherapy detection assay epithelial to mesenchymal transition insight malignant breast neoplasm mammary migration mouse model mutant mutation carrier novel strategies overexpression prevent progenitor therapeutic target trait transcription factor tumorigenesis

项目摘要

Abstract Basal-like breast cancer (BLBC) consistently expresses genes typical of normal basal/myoepithelial cells of the breast and comprises up to 25% of all breast cancer. It is associated with aggressive clinical behavior and a high rate of metastasis to the lung. The organ-preferential metastasis of BLBC is poorly understood. Of note, the vast majority of breast tumors arising in BRCA1 mutation carriers display a basal-like phenotype. Little is currently known about the molecular basis of the tissue and subtype-specific features of BRCA1-mutant breast cancer. We found that the transcription factor FOXC1 is exclusively induced in BLBC including BRCA1-mutant breast cancer and correlates with poor clinical outcome. It regulates breast cancer cell function by inducing NF- κB and other cancer-associated signaling pathways. Its overexpression in the mouse mammary gland increases the luminal progenitor population, which is postulated to be the cell of origin of BRCA1-mutant breast cancer. We also found that FOXC1 and its targets CXCL1, 2, and 8 chemokines are essential for BLBC lung metastasis. These chemokines act in concert with lung fibroblasts to induce endothelial cell migration in vitro. We therefore hypothesize that FOXC1 counteracts the detrimental effects of BRCA1 mutations in breast cells and plays a critical role in basal-like BRCA1-mutant breast cancer development. In addition, we hypothesize that the chemokines CXCL1, 2, and 8 mediate the effect of FOXC1 on BLBC lung metastasis by engaging lung fibroblasts to induce angiogenesis. In Aim 1, we will determine the role of FOXC1 in the development of BRCA1-mutant breast cancer with the basal-like phenotype. BRCA1-mutant breast cancer cell models will be used to test whether FOXC1 signaling pathways regulate cell function and counteracts the increase of reactive oxygen species in breast epithelial cells with BRCA1 mutations or deficiency. We will determine whether FOXC1 regulates mammary tumorigenesis in BRCA1-mutant xenograft models and a mammary-specific BRCA1-deficient mouse model. In Aim 2, we will define a FOXC1/chemokine-mediated mechanism for BLBC lung metastasis. Tail vein injection mouse models will be used to investigate whether the FOXC1-induced chemokines promote the proliferation and survival of metastatic breast cancer cells in the lung tissue microenvironment. We will determine whether FOXC1 overexpression in BLBC leads to increased angiogenesis in lung metastases mediated by chemokine-directed crosstalk between metastatic breast cancer cells and lung fibroblasts. We will further investigate the mechanism whereby FOXC1 regulates the three chemokines in BLBC cells. Basal-like BRCA1-mutant breast cancer development and BLBC metastasis are poorly understood areas that are of paramount importance in breast cancer. Our results will shed light on their biological basis and will lay down a foundation for new approaches that can prevent and treat FOXC1- overexpressing breast cancer.

摘要基底样乳腺癌（BLBC）始终表达正常基底/肌上皮细胞的典型基因，乳腺癌占所有乳腺癌的25%。它与攻击性临床行为和肺转移率高。BLBC的器官优先转移知之甚少。值得注意的是，绝大多数BRCA 1突变携带者产生的乳腺肿瘤显示出基底样表型。之甚少目前已知BRCA 1突变乳腺癌的组织和亚型特异性特征的分子基础，癌我们发现转录因子FOXC 1只在BLBC中被诱导，包括BRCA 1突变体，乳腺癌和相关的临床结果差。它通过诱导NF-κ B的表达来调节乳腺癌细胞的功能。 κB和其他癌症相关信号通路。其在小鼠乳腺中的过度表达增加管腔祖细胞数量，这被认为是BRCA 1突变乳腺癌的起源细胞癌我们还发现FOXC 1及其靶点CXCL 1、2和8趋化因子对BLBC肺是必需的转移这些趋化因子在体外与肺成纤维细胞协同作用以诱导内皮细胞迁移。因此，我们假设FOXC 1抵消了乳腺细胞中BRCA 1突变的不利影响，并在基底样BRCA 1突变型乳腺癌的发展中起关键作用。另外，我们假设趋化因子CXCL 1、CXCL 2和CXCL 8介导FOXC 1对BLBC肺转移的作用，成纤维细胞以诱导血管生成。在目标1中，我们将确定FOXC 1在以下发展中的作用： BRCA 1突变型乳腺癌伴基底细胞样表型BRCA 1突变乳腺癌细胞模型将被用于测试FOXC 1信号通路是否调节细胞功能，并抵消反应性 BRCA 1突变或缺陷的乳腺上皮细胞中的氧物种。我们将决定 FOXC 1在BRCA 1突变异种移植模型中调节乳腺肿瘤发生， BRCA 1缺陷小鼠模型。在目标2中，我们将定义FOXC 1/趋化因子介导的BLBC机制肺转移尾静脉注射小鼠模型将被用于研究FOXC 1诱导的F0 XC 1表达是否被抑制。趋化因子促进肺组织中转移性乳腺癌细胞的增殖和存活微环境。我们将确定BLBC中FOXC 1的过表达是否会导致趋化因子介导的转移性乳腺癌与肺转移瘤的血管生成细胞和肺成纤维细胞。我们将进一步研究FOXC 1调节这三种蛋白的机制。 BLBC细胞中的趋化因子。基底样BRCA 1突变乳腺癌的发生和BLBC转移是对乳腺癌中至关重要的领域知之甚少。我们的研究结果将有助于生物学基础，并将为预防和治疗FOXC 1的新方法奠定基础，过度表达乳腺癌

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer.

DOI：
10.1186/s12964-016-0148-8
发表时间：
2016-10-21
期刊：
Cell communication and signaling : CCS
影响因子：
0
作者：
Farabaugh SM;Chan BT;Cui X;Dearth RK;Lee AV
通讯作者：
Lee AV

Human fibroblasts facilitate the generation of iPSCs-derived mammary-like organoids.

DOI：
10.1186/s13287-022-03023-7
发表时间：
2022-07-28
期刊：
Stem cell research & therapy
影响因子：
7.5
作者：
通讯作者：

Adjacent skin rotation flap for large defect in primary breast tumor.

DOI：
10.1002/jso.25240
发表时间：
2018-12
期刊：
Journal of surgical oncology
影响因子：
2.5
作者：
Jin L;Wu X;Zha L;Feng Y;Xu J;Zheng H;Shao J;Zhao M;Cui X;Giuliano AE;Gong Y
通讯作者：
Gong Y

The biomarkers changes in serum and the correlation with quantitative MRI markers by histopathologic evaluation of the cartilage in surgically-induced osteoarthritis rabbit model.

通过对手术诱导的骨关节炎兔模型中的软骨进行组织病理学评估，观察血清中生物标志物的变化以及与定量 MRI 标志物的相关性。

DOI：
10.1371/journal.pone.0124717
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Zuo H;Jiang L;Qu N;Wang J;Cui X;Yao W
通讯作者：
Yao W

FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer.

DOI：
10.1245/s10434-014-3980-3
发表时间：
2014-12
期刊：
Annals of surgical oncology
影响因子：
3.7
作者：
Jin Y;Han B;Chen J;Wiedemeyer R;Orsulic S;Bose S;Zhang X;Karlan BY;Giuliano AE;Cui Y;Cui X
通讯作者：
Cui X