Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer

总结 背景三阴性乳腺癌（TNBC）表现为晚期组织学分级， 攻击性临床行为他们对传统的全身治疗反应迟钝， 患有难治性疾病的患者具有增加的复发率和令人沮丧的5年存活率。可靠 因此，迫切需要TNBC的生物标志物和靶向疗法，但仍有待定义。 初步调查结果。我们发现PTX 3在TNBC标本和患者中特别丰富。 来源的异种移植物（PDX），并且其水平与不良TNBC患者的 生存我们发现，PTX 3增殖了癌症干细胞（CSC）样特征，它促进了癌细胞的增殖， 在悬浮液中生长，并且其促进TNBC转移的多倍增加。此外，我们证明 PTX 3激活抗凋亡途径并使TNBC细胞对化疗脱敏。遗传 抑制PTX 3可抑制癌基因诱导的细胞生长，并平息TNBC细胞的恶性特征， 例如迁移和锚定独立生长。重要的是，我们发现循环中的PTX 3水平， 其由TNBC细胞分泌，与临床前模型中的肿瘤负荷相关， 在TNBC患者中升高。最后，我们表明PTX 3的抗体中和引起TNBC细胞死亡。 假设。我们假设PTX 3是TNBC患者风险分层的关键生物标志物， 它是恶性肿瘤的决定性功能驱动因素，也是转化利用的易处理的治疗靶点， TNBC管理。 具体目标和研究设计。我们将建立PTX 3作为临床TNBC的预后生物标志物（目的是 1），确定PTX 3如何调节恶性进展（目的2），并将PTX 3确定为TNBC治疗剂 具体目标（目标3）。为此，我们将肿瘤和循环中PTX 3的水平与患者的存活率相关联， 采用PCR、原位和ELISA方法对大型TNBC患者队列进行回顾性分析 (aims 1.1和1.2）。然后，我们将确定PTX 3在调节自我更新和肿瘤启动中的作用。 CSCs的功能（目的2.1），确定PTX 3促进的转移步骤（目的2.2），并评估其 在体外和体内对化疗耐药性的贡献（目标2.3）。最后，我们将确定 PTX 3对使用异种移植物的已建立转移瘤的起始（目的3.1）、存活和生长（目的3.2）的影响 模型，以及研究抗PTX 3中和抗体抑制致瘤性生长的能力 使用患者来源的异种移植物和同系小鼠癌症模型（aim 3.3）。 冲击我们所寻求的结果将介绍新的治疗诊断学的潜在突破性效用，在管理 侵袭性和难以治疗的乳腺癌，迫切需要靶向治疗。

SUMMARY Background. Triple-negative breast cancers (TNBCs) present with advanced histological grade and aggressive clinical behavior. They are overwhelmingly unresponsive to conventional systemic treatments, and patients with refractory disease have increased recurrence and dismal 5-year survival rates. Reliable biomarkers and targeted therapies for TNBC are therefore critically needed, but remain to be defined. Preliminary findings. We found that PTX3 was particularly abundant in TNBC specimens and in patient- derived xenografts (PDX), and that its levels positively and specifically correlated with adverse TNBC patient survival. We show that PTX3 propagated cancer-stem-cell (CSC) -like traits, that it promoted cancer cell growth in suspension, and that it promoted multifold increase in TNBC metastasis. In addition, we demonstrate that PTX3 activated anti-apoptotic pathways and de-sensitized TNBC cells to chemotherapy. Genetic suppression of PTX3 inhibited oncogene-induced cell growth, and quelled malignant features of TNBC cells, such as migration and anchorage-independent growth. Importantly, we show that circulating levels of PTX3, which is secreted by TNBC cells, associated with tumor burden in preclinical models and were particularly elevated in TNBC patients. Finally, we show that antibody neutralization of PTX3 caused TNBC cell death. Hypotheses. We hypothesize that PTX3 is a critical biomarker for risk stratification of TNBC patients, and that it is a decisive functional driver of malignancy and a tractable therapeutic target of translational utility in TNBC management. Specific aims and study design. We will establish PTX3 as a prognostic biomarker in clinical TNBC (aim 1), determine how PTX3 regulates malignant progression (aim 2), and establish PTX3 as a TNBC therapeutic target (aim 3). To this end, we will correlate tumoral and circulating levels of PTX3 to patient survival in retrospective analyses of a large TNBC patient cohort using PCR-, -in situ, and ELISA-based approaches (aims 1.1 and 1.2). We will then determine the role of PTX3 in regulating self-renewal and tumor-initiating functions of CSCs (aim 2.1), identify the metastatic steps facilitated by PTX3 (aim 2.2) and assess its contributions to chemoresistance in vitro and in vivo (aim 2.3). Finally, we will determine the essentiality of PTX3 to the initiation (aim 3.1), survival, and growth of established metastases (aim 3.2) using xenograft models, as well as investigate the ability of anti-PTX3 neutralizing antibodies to suppress tumorigenic growth using patient-derived xenograft and syngeneic murine cancer models (aim 3.3). Impact. Our sought results will introduce novel theranostics of potential groundbreaking utility in managing aggressive and difficult-to-treat breast cancers for which targeted therapies are sorely needed.