The Perinucleolar Compartment as Breast Cancer Marker

描述（由申请人提供） 目前，预后和预测癌症标志物不足，导致大部分患者，特别是处于疾病早期阶段的患者治疗过度或治疗不足。该建议的目的是评估核仁周围区室（PNC），一种多组分细胞结构，作为临床前环境中的预后和预测肿瘤标志物。我们的初步研究结果表明，PNC患病率（细胞中含有至少一个PNC的百分比）与培养细胞和体内乳腺肿瘤的恶性表型相关。PNC患病率随着乳腺癌疾病进展而增加，并且在远处转移中最高。多变量分析（加上大小和等级）表明，原发肿瘤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淋巴结或<4个阳性淋巴结病例中高于23%的患者。此外，PNC对化疗药物的子集高度敏感。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，因此它可能是一个理想的候选人作为肿瘤标志物。这项资助计划中提出的工作将检验这一假设。特定目的将通过检查PNC患病率与类似诊断乳腺癌患者的无病生存率和总生存率之间的关系，评估并确认PNC患病率的预后能力。研究还将通过比较用降低培养细胞中PNC患病率的药物治疗的患者的结果与未经治疗或用对PNC没有影响的药物治疗的患者的结果来评估PNC患病率的预测能力。我们希望拟议的研究将澄清PNC，一种容易检测的细胞结构，是否可以提高与现有标志物联合使用时乳腺癌预后和预测的准确性。

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.