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

• 批准号: 9149174
• 负责人: Ritu Aneja
• 金额: $ 30.71万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 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/9149174
• 关键词: Address; Adriamycin PFS; Affect; African American; Aggressive Clinical Course; Biologic Characteristic; Biological; Boxing; 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; Diagnostic Neoplasm Staging; Disease; Disease Outcome; Distant; Epithelial Cells; Evaluation; Fine needle aspiration biopsy; Formalin; Gene Expression Profile; Goals; Golgi Apparatus; Griseofulvin; Health; 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; Second Primary Cancers; Severities; Site; Staging; Subgroup; Testing; Time; Tissues; Treatment Protocols; Tumor Biology; Tumor stage; Vimentin; Woman; 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; receptor; small molecule; success; targeted treatment; trafficking; trait; tumor; tumor growth

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（由申请人提供）：与白人妇女相比，AA妇女的乳腺癌具有发病早、侵袭性高、转移范围广、死亡率高的特点。临床医生和癌症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变为侵袭性肿瘤，并很容易转移到身体的远处。一种简单可靠的预测方法