The role of FOXC1 in basal-like breast cancer

FOXC1 在基底样乳腺癌中的作用

• 批准号: 8827694
• 负责人: Xiaojiang Cui
• 金额: $ 34.65万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-14 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827694
• 关键词: 4T1; Affect; African American; Area; BRCA1 gene; Basal Cell; Behavior; Biological; Biological Markers; Brain; Breast Cancer Cell; Breast Cancer Treatment; Breast Epithelial Cells; Breast cancer metastasis; Cell Proliferation; Cell model; Cell physiology; Cells; Characteristics; Classification; Clinical; Cytokeratin; Detection; Development; Diagnosis; Down-Regulation; EGF gene; ERBB2 gene; Embryonic Development; Estrogen Receptors; Estrogen receptor negative; Gene Expression; Genes; Genetic Transcription; Goals; Human; Immunohistochemistry; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Modality; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Mutation; Myoepithelial; Myoepithelial cell; NF-kappa B; Neoplasm Metastasis; Phenotype; Progesterone Receptors; Property; Proteins; Regulation; Role; Signal Transduction; Stem cells; Subgroup; Surrogate Markers; Systemic Therapy; Testing; Therapeutic; Transgenic Mice; Up-Regulation; Woman; Xenograft Model; base; beta catenin; cell growth; chemotherapy; clinical investigation; epithelial to mesenchymal transition; in vivo; insight; lymph nodes; malignant breast neoplasm; migration; molecular marker; mouse model; notch protein; outcome forecast; overexpression; p65; prevent; public health relevance; self-renewal; stem; trait; transcription factor; tumor; young woman

DESCRIPTION (provided by applicant): Basal-like breast cancers (BLBCs) express genes characteristic of myoepithelial/basal cells in the normal mammary gland and comprise up to 25% of all breast cancers. Chemotherapy is the only systemic therapy for BLBC, which underexpresses estrogen receptor (ER), progesterone receptor, and HER-2. It preferentially affects younger women and African-American women, and is associated with high histological grade, aggressive clinical behavior, and a high rate of metastasis to the lung and brain. Unlike other breast cancer subtypes, there is no correlation between tumor size and lymph node metastasis. To date, little is known about the molecular basis of BLBC. We have found that the transcription factor FOXC1, which is involved in embryonic development, is consistently and exclusively induced in BLBC and is associated with poor overall survival. FOXC1 overexpression in normal breast epithelial cells and breast cancer cells increased cell proliferation, migration, invasion, and protein levels of NF-kB p65 and β-catenin. We therefore hypothesize that FOXC1 is a critical marker and functional regulator of BLBC via modulating NF-kB activation and β-catenin signaling. In addition, we hypothesize that expression of FOXC1, repressed by ER but elicited by ERK/Notch signaling, determines the propensity of BLBC to metastasize to the brain and lung. In Aim 1, we will determine whether FOXC1 regulates cell growth, migration, invasion, and stem cell-like properties of BLBC cells by activating NF-kB and β-catenin signaling. FOXC1 overexpression and knockdown cell models will be used to examine the mechanisms and effects of the upregulation of p65 and β-catenin by FOXC1. In Aim 2, we will determine whether FOXC1 regulates BLBC development in vivo and predisposes breast cancer to brain and lung metastasis. The MMTV-FOXC1 transgenic mouse model will be used to investigate the role of FOXC1 in BLBC development. A brain-seeking xenograft model and the metastatic 4T1 syngeneic mouse mode will be used to study whether FOXC1 governs preferential BLBC metastasis to the brain and lung, respectively. In Aim 3, we will define the molecular mechanisms responsible for upstream regulation of FOXC1 overexpression in BLBC. We will investigate whether EGF induces FOXC1 expression in BLBC cells through downstream ERK and Notch signaling, and whether Notch and ER mediate BRCA1 inhibition of FOXC1 transcription. BLBC is a poorly understood area that is of paramount importance in breast cancer. By providing insight into the biological mechanism for BLBC, this study will facilitate establishing a critical functional marker for detection and diagnosis of BLBC. Results may warrant development and clinical investigation of agents that block FOXC1. Finally, understanding how FOXC1 expression is regulated may allow development of FOXC1-based strategies to prevent BLBC.

描述（由申请人提供）：基底样乳腺癌（BLBC）表达正常乳腺中肌上皮/基底细胞的特征性基因，占所有乳腺癌的25%。化疗是BLBC的唯一全身治疗方法，BLBC低表达雌激素受体（ER），孕激素受体和HER-2。它优先影响年轻女性和非洲裔美国女性，并与高组织学分级，侵袭性临床行为和高肺和脑转移率相关。与其他乳腺癌亚型不同，肿瘤大小与淋巴结转移无关。迄今为止，对BLBC的分子基础知之甚少。我们已经发现，转录因子FOXC 1，这是参与胚胎发育，是一贯和专门诱导BLBC和相关的整体生存率低。FOXC 1在正常乳腺上皮细胞和乳腺癌细胞中的过表达增加了细胞增殖、迁移、侵袭以及NF-κ B p65和β-连环蛋白的蛋白水平。 因此，我们假设FOXC 1是BLBC的关键标志物和功能调节因子，通过调节NF-κ B活化和β-catenin信号传导。此外，我们假设FOXC 1的表达，ER抑制，但引起ERK/Notch信号，决定BLBC转移到脑和肺的倾向。在目标1中，我们将确定FOXC 1是否通过激活NF-κ B和β-catenin信号传导来调节BLBC细胞的细胞生长、迁移、侵袭和干细胞样特性。FOXC 1过表达和敲低细胞模型将用于检查FOXC 1上调p65和β-连环蛋白的机制和作用。在目标2中，我们将确定FOXC 1是否在体内调节BLBC的发展，并使乳腺癌易于发生脑和肺转移。将使用MMTV-FOXC 1转基因小鼠模型来研究FOXC 1在BLBC发育中的作用。寻找大脑的异种移植模型和转移性4 T1同基因小鼠模型将用于研究FOXC 1是否分别支配BLBC向大脑和肺的优先转移。在目标3中，我们将确定负责上游调控BLBC中FOXC 1过表达的分子机制。我们将研究EGF是否通过下游ERK和Notch信号诱导BLBC细胞中FOXC 1的表达，以及Notch和ER是否介导BRCA 1抑制FOXC 1转录。 BLBC是一个知之甚少的领域，在乳腺癌中至关重要。通过对BLBC生物学机制的深入了解，本研究将有助于建立BLBC检测和诊断的关键功能标志物。这些结果可能会证明阻断FOXC 1的药物的开发和临床研究是有必要的。最后，了解FOXC 1的表达是如何调节的，可能有助于开发基于FOXC 1的预防BLBC的策略。