The Perinucleolar Compartment as Breast Cancer Marker

描述(由申请人提供) 目前预测和预测癌症的标记物不足，导致很大比例的患者治疗过度或治疗不足，特别是那些处于疾病早期阶段的患者。这项建议的目的是评估核周间隔(PNC)，一种多组分的细胞结构，在临床前环境中作为预后和预测肿瘤标记物。我们的初步发现表明，PNC的患病率(细胞中至少含有一个PNC的百分比)与培养细胞和体内乳腺肿瘤的恶性表型有关。PNC的患病率与乳腺癌的疾病进展同步增加，在远处转移中最高。多因素分析(加上大小和分级)显示，原发癌PNC患病率低于23%的乳腺癌患者的无病生存率显著高于阴性结节或阳性结节高于23%的患者。此外，PNC对化疗药物的一个子集高度敏感。这些结果表明，PNC反映了癌细胞的整体恶性行为，并具有独立的预后价值，是一种理想的肿瘤标志物。这项拨款中提出的工作将检验这一假设。具体目的将通过检查PNC患病率与类似诊断的乳腺癌患者的无病生存率和总存活率之间的关系，来评估和确认PNC患病率的预后能力。研究还将评估PNC患病率的预测能力，方法是将接受降低培养细胞PNC患病率的药物治疗的患者的结果与未治疗或使用对PNC没有影响的药物治疗的患者的结果进行比较。我们预计，拟议的研究将澄清PNC，一种容易检测的细胞结构，是否可以提高乳腺癌预后和预测的准确性，当与现有的标志物结合使用时。

DESCRIPTION (provided by applicant) Currently prognostic and predictive cancer markers are inadequate, resulting in over or under treatment of a large percentage of patients, particularly those at early stages of diseases. The goal of this proposal is to evaluate the perinucleolar compartment (PNC), a multi-component cellular structure, as a prognostic and predictive tumor marker in a pre-clinical setting. Our preliminary findings demonstrate that PNC prevalence (the percentage of cells contains at least one PNC) associates with the malignant phenotype both in cultured cells and in vivo in breast tumors. PNC prevalence increases in parallel with the disease progression of breast cancer and is highest in distant metastases. Multivariate analyses (adding onto size and grade) demonstrate that breast cancer patients having primary tumors with a PNC prevalence below 23% show a significantly better disease free survival rate than those above 23% in the cases with negative nodes or <4 positive nodes. Furthermore, the PNC is highly sensitive to a subset of chemotherapeutic drugs. These findings suggest that the PNC reflects the overall malignant behaviors of cancer cells and contains independent prognostic value, thus it could be an ideal candidate as a tumor marker. Work proposed in this grant will test this hypothesis. The Specific Aims will evaluate and confirm the prognostic power of PNC prevalence by examining the relationship between this marker and disease free and overall survival rate in similarly diagnosed breast cancer patients. Studies will also assess the predictive power of PNC prevalence by comparing the outcomes of patients who are treated with drugs that reduce PNC prevalence in cultured cells vs. the outcomes of those untreated or treated with drugs that have no effect on PNCs. We expect the proposed studies will clarify whether the PNC, an easily detectable cellular structure, could improve the accuracy of breast cancer prognosis and prediction when used in combination with existing markers.