The role of FOXC1 in basal-like breast cancer

描述(申请人提供)：基底细胞样乳腺癌(BLBC)表达正常乳腺中肌上皮细胞/基底细胞的特征基因，占所有乳腺癌的25%。化疗是BLBC唯一的全身治疗方法，它低表达雌激素受体(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有关。与其他乳腺癌亚型不同，肿瘤大小和淋巴结转移之间没有相关性。迄今为止，人们对BLBC的分子基础知之甚少。我们已经发现，参与胚胎发育的转录因子FOXC1在BLBC中持续且唯一地诱导，并与较差的总体存活率相关。FOXC1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的增殖、迁移、侵袭以及核因子-kB p65和β-连环蛋白的蛋白水平。 因此，我们推测FOXC1是BLBC的关键标志物和功能调节因子，通过调节核因子-kB的激活和β-连环蛋白信号转导。此外，我们假设FOXC1的表达受ER抑制，但由ERK/Notch信号诱导，决定了BLBC转移到脑和肺的倾向。在目标1中，我们将确定FOXC1是否通过激活NF-kB和β-catenin信号来调节BLBC细胞的生长、迁移、侵袭和干细胞样特性。FOXC1超表达和基因敲除细胞模型将被用来研究FOXC1p65和β-catenin上调的机制和作用。在目标2中，我们将确定FOXC1是否在体内调节BLBC的发展，并使乳腺癌容易发生脑和肺转移。将利用MMTV-FOXC1转基因小鼠模型来研究FOXC1在BLBC发育中的作用。将使用异种脑移植模型和转移性4T1同基因小鼠模型来研究FOXC1是否分别控制BLBC向脑和肺的优先转移。在目标3中，我们将定义在BLBC中负责FOXC1过度表达上游调控的分子机制。我们将研究EGF是否通过下游的ERK和Notch信号诱导BLBC细胞FOXC1的表达，以及Notch和ER是否介导BRCA1抑制FOXC1的转录。 BLBC是一个知之甚少的区域，在乳腺癌中起着至关重要的作用。通过对BLBC的生物学机制的深入研究，本研究将有助于建立BLBC的检测和诊断的关键功能标记。研究结果可能为FOXC1阻滞剂的开发和临床研究提供依据。最后，了解FOXC1表达是如何调控的，可能有助于开发基于FOXC1的预防BLBC的策略。 公共卫生相关性：基底细胞样乳腺癌是乳腺癌的一种亚型，预后最差，人们对此知之甚少。化疗是这些乳腺癌唯一的全身治疗方法。我们的研究将有助于建立检测和诊断基底细胞样癌的关键分子标记，并有助于揭示基底细胞样乳腺癌细胞特征和表型的生物学基础。

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 ?-catenin. We therefore hypothesize that FOXC1 is a critical marker and functional regulator of BLBC via modulating NF-kB activation and ?-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 ?-catenin signaling. FOXC1 overexpression and knockdown cell models will be used to examine the mechanisms and effects of the upregulation of p65 and ?-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. PUBLIC HEALTH RELEVANCE: Basal-like breast cancer is a subtype of breast cancer which has the worst prognosis and is poorly understood. Chemotherapy is the only systemic treatment for these breast cancers. Our study will help establish a critical molecular marker for detection and diagnosis of basal-like cancers, and also help uncover the biological basis for the cellular traits and phenotypes of basal-like breast cancer.