The Role of FOXCI in Basal-like Breast Cancer

摘要 基底细胞样乳腺癌(BLBC)持续表达正常乳腺基底/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的器官优先转移机制尚不清楚。值得注意的是， 绝大多数发生在BRCA1突变携带者的乳腺肿瘤表现为基底样表型。小才是 目前已知BRCA1突变乳房的组织分子基础和亚型特异性特征 癌症。我们发现转录因子FOXC1只在BLBC中被诱导，包括BRCA1-突变体 乳腺癌，并与不良的临床结果相关。它通过诱导核因子-2来调节乳腺癌细胞的功能 κB和其他与癌症相关的信号通路。它在小鼠乳腺中的过表达 增加腔祖细胞的数量，这被认为是BRCA1突变乳房的起源细胞 癌症。我们还发现FOXC1及其靶分子CXCL1、2和8对BLBC肺是必不可少的 转移。这些趋化因子与肺成纤维细胞协同作用，在体外诱导内皮细胞迁移。 因此，我们假设FOXC1可以抵消乳腺细胞中BRCA1突变的有害影响 并且在基底样型BRCA1突变乳腺癌的发生中起关键作用。此外，我们假设 趋化因子CXCL1、CXCL2和CXCL8介导FOXC1通过肺转移抑制BLBC肺转移 成纤维细胞诱导血管生成。在目标1中，我们将确定FOXC1在 BRCA1-突变型乳腺癌，具有基底样表型。BRCA1突变的乳腺癌细胞模型将是 用来测试FOXC1信号通路是否调节细胞功能并抵消反应性增加 BRCA1突变或缺失的乳腺上皮细胞中的氧物种。我们将确定是否 FOXC1对BRCA1突变型异种移植模型乳腺肿瘤发生的调控作用 BRCA1缺陷小鼠模型。在目标2中，我们将定义FOXC1/趋化因子介导的BLBC机制 肺转移。将采用小鼠尾静脉注射FOXC_1模型，研究FOXC_1诱导的 趋化因子促进肺组织转移性乳腺癌细胞的增殖和存活 微环境。我们将确定FOXC1在BLBC中的过度表达是否会导致 趋化因子介导的转移性乳腺癌肺转移中的血管生成 细胞和肺成纤维细胞。我们将进一步研究FOXC1调节这三个因素的机制 BLBC细胞中的趋化因子基底细胞样BRCA1突变乳腺癌的发生和BLBC转移 人们对乳腺癌中至关重要的区域知之甚少。我们的结果将揭示他们的 并将为预防和治疗FOXC1的新方法奠定基础- 过度表达乳腺癌。

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.