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

描述(申请人提供)：与高加索女性相比，AA女性乳腺癌的特点是发病更早，侵袭性更强，转移范围更广，死亡率更高。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，很容易转移到身体的远处。一种简单可靠的预测测试 到目前为止，早期肿瘤的转移风险仍然难以捉摸。显然，关键障碍是 进展是缺乏对非侵入性病变的可量化特性的了解，这些特性可以预测 更快发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背后的细胞生物学特征来解决这一重要的知识差距，从而减少非裔美国人(AA)和高加索女性之间与乳腺癌相关的健康差距。我们的中心假设是，放大的中心体通过组织一个紧凑的高尔基网络来增强细胞极化，该网络推动定向细胞迁移和侵袭，以加速转移。不同转移潜能的肿瘤之间可能存在器官水平的差异，这一诱人的可能性从未被探索过。我们的CA促进转移的新范式是一项突破性的概念进步，在早期风险预测中具有翻译前景。我们的项目将加强对1)确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)细胞获得转移基础的迁移和侵袭能力的机制。我们的研究将对以下方面产生影响：1)快速、非侵入性的中心体检测方法(如细针吸取细胞学)，这种方法将能够早期区分临床上无痛和潜在致命的乳腺癌，从而使无痛疾病患者免于不必要的乳房切除术；b)早期将患者分成具有不同中心体特征的亚组的方法，对乳腺癌进行有效的风险适应治疗；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的成功率。目标1将 建立非裔美国人和高加索女性受体匹配和分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。目的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，这将特别有利于再生障碍性贫血妇女，并减少疾病结局中的种族差异。

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.