Evaluation of centrosome amplification as a risk-predictor for breast cancer aggr

描述（由申请人提供）：与高加索女性相比，AA女性乳腺癌的特征是发病早、侵袭性高、转移更广泛和死亡率增加。临床医生和癌细胞生物学家都面临着一个令人困惑的谜团，那就是为什么一些非侵袭性乳腺癌会转化为侵袭性肿瘤，并容易转移到体内的远处。一个简单可靠的测试来预测 早期肿瘤的转移风险至今仍然难以捉摸。很明显， 进展是缺乏对非侵入性病变的可量化特性的知识，这些特性可预测 更快的动力学进展为转移性疾病的可能性。我们的目标是通过确定疾病侵袭性的细胞生物学特征来解决这一重要的知识差距，从而减少非洲裔美国人（AA）和高加索妇女之间与乳腺癌相关的健康差距。我们的中心假设指出，扩增的中心体通过组织一个紧凑的高尔基体网络，推动定向细胞迁移和入侵，加速转移，从而增强细胞极化。细胞器水平的差异可能存在于不同转移潜能的肿瘤之间，这一诱人的可能性从未被探索过。我们的新范式，CA促进转移是一个突破性的概念进步，它在早期风险预测中具有转化的希望。我们的项目将提高对1）决定转移风险的非侵入性病变的细胞生物学特征的理解，以及2）细胞获得转移的迁移和侵入能力的机制。我们的研究将对发展1）快速，非侵入性的基于中心体的检测方法产生影响（例如细针抽吸细胞学），其将允许临床惰性和潜在致命性乳腺癌之间的早期区分，从而使患有惰性疾病的患者免于不必要的乳房切除术，B）用于将患者早期分层为具有不同中心体谱的亚组的方法，c）通过建立新的患者分类标准，提高涉及研究药物的临床试验成功率的框架。AIM 1将 建立非裔美国人和高加索妇女受体和等级匹配的乳腺肿瘤之间中心体扩增的发生率和严重程度的差异。AIM 2将确定将扩增的中心体与更具侵袭性的肿瘤表型联系起来的分子机制。AIM 3将在临床前开发针对侵袭性乳腺癌的小分子中心体靶向疗法，这将特别有利于AA女性，并减少疾病结局的种族差异。

DESCRIPTION (provided by applicant): Breast cancers in AA women are characterized by earlier onset, higher aggressiveness, more extensive metastases, and increased mortality rates compared to those in Caucasian women. A bewildering mystery confronting clinicians and cancer cell biologists alike is why some non-invasive breast cancers transform into aggressive tumors that readily metastasize to distant sites in the body. A simple and reliable test to predict metastatic risk in early-stage tumors has so far remained elusive. Clearly, the critical barrier to progress is a lack of knowledge of quantifiable properties of non-invasive lesions that predict the probability of faster kinetic progression to metastatic disease. Our goal is to address this vital knowledge gap by identifying cell biological characteristics underlying the disease's aggressiveness, thereby reducing the breast cancer-related health disparity between African American (AA) and Caucasian women. Our central hypothesis states that amplified centrosomes enhance cell polarization by organizing a compacted Golgi network that propels directed cell migration and invasion to accelerate metastases. The tantalizing possibility that organellar-level disparities may exist between tumors of differing metastatic potential has never been explored. Our novel paradigm that CA promotes metastasis is a groundbreaking conceptual advancement, which holds translational promise in early risk prediction. Our project will enhance understanding of 1) cell-biological traits of non-invasive lesions that determine metastatic risk, and 2) mechanisms by which cells acquire migratory and invasive capabilities that underlie metastases. The impact of our study will be on the development of 1) rapid, non-invasive centrosome-based detection methods (e.g. fine-needle aspirate cytology) which will allow early distinction between clinically-indolent and potentially fatal breast cancers, thus saving patients with indolent disease from unnecessary mastectomy, b) a method for early stratification of patients into subgroups with distinct centrosomal profiles, for effective risk-adapted treatment of breast cancer, c) a framework for improving success rate of clinical trials involving investigational drugs by establishing new criteria for patient classification. AIM 1 will establish differences in the incidence and severity of centrosome amplification between receptor- and grade-matched breast tumors from African American and Caucasian women. AIM 2 will determine molecular mechanisms that link amplified centrosomes to more aggressive tumor phenotypes. AIM 3 will pre-clinically develop small-molecule centrosome-targeted therapies for aggressive breast cancers, which will particularly benefit AA women, and reduce ethnic disparity in disease outcomes.