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

中心体扩增作为乳腺癌聚集风险预测的评估

基本信息

批准号：
9339617
负责人：
Ritu Aneja
金额：
$ 30.32万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339617
关键词：
Address Adriamycin PFS Affect African American Aggressive Clinical Course Archives Biologic Characteristic Biological Breast Cancer Cell Breast Cancer Treatment Cancer Etiology Caucasians Cell Death Cell Polarity Cells Centrosome Cessation of life Classification Clinic Clinical Clinical Trials Complement Cytology Cytoskeleton Data Detection Development Disease Disease Outcome Distant Epithelial Cells Evaluation Fine needle aspiration biopsy Formalin Gene Expression Profile Goals Golgi Apparatus Griseofulvin Image Immunofluorescence Immunologic Implant In Vitro Incidence Indolent Investigational Drugs Kinetics Knowledge Lead Link Luciferases Mammary Neoplasms Mastectomy Metastatic to Methods Microtubules Molecular Mus Neoplasm Metastasis Non-Invasive Lesion Normal Cell Organelles Paraffin Embedding Patient-Focused Outcomes Patients Personality Pharmaceutical Preparations Phenotype Play Probability Progression-Free Survivals Property Reporting Research Risk S Phase Sampling Savings Severities Site Subgroup Testing Time Tissues Treatment Protocols Tumor Biology Tumor stage Vimentin Woman aggressive therapy base cancer cell cancer diagnosis cell motility cellular engineering clinical practice cohort docetaxel drug standard early onset ethnic disparity health disparity high risk implantation improved in vivo malignant breast neoplasm migration mortality novel patient stratification polarized cell pre-clinical public health relevance receptor small molecule success targeted treatment trafficking trait tumor tumor growth

项目摘要

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.

描述（申请人提供）：与白人女性相比，AA 女性乳腺癌的特点是发病更早、侵袭性更强、转移更广泛、死亡率更高。临床医生和癌细胞生物学家面临的一个令人困惑的谜团是，为什么一些非侵袭性乳腺癌会转变为侵袭性肿瘤，并且很容易转移到身体的远处部位。简单可靠的预测测试迄今为止，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的动力学进展为转移性疾病的可能性。我们的目标是通过识别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) 和白人女性之间与乳腺癌相关的健康差异。我们的中心假设指出，扩增的中心体通过组织紧凑的高尔基体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。不同转移潜力的肿瘤之间可能存在细胞器水平差异的诱人可能性从未被探索过。我们的 CA 促进转移的新范式是一个突破性的概念进步，它在早期风险预测中具有转化前景。我们的项目将加深对 1) 决定转移风险的非侵袭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。我们的研究将影响以下方面的发展：1）快速、非侵入性的基于中心体的检测方法（例如细针抽吸细胞学），这将有助于早期区分临床惰性乳腺癌和可能致命的乳腺癌，从而挽救患有癌症的患者。不必要的乳房切除术引起的惰性疾病，b）一种将患者早期分层为具有不同中心体特征的亚组的方法，用于有效的乳腺癌风险适应治疗，c）提高成功率的框架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率。目标 1 将确定非裔美国人和白人女性的受体和级别匹配的乳腺肿瘤之间中心体扩增的发生率和严重程度存在差异。 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 将针对侵袭性乳腺癌进行临床前开发小分子中心体靶向疗法，这将特别有利于 AA 女性，并减少疾病结果的种族差异。