CD13 as a Biomaker for Chemoprevention of Breast Cancer

CD13 作为乳腺癌化学预防的生物制造者

• 批准号: 7620059
• 负责人: LINDA H SHAPIRO
• 金额: $ 27.72万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7620059
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Apoptosis; Binding; Biological Markers; Biopsy Specimen; Breast Cancer Cell; Breast Cancer Prevention; Breast Carcinoma; Cell Nucleus; Cell physiology; Cell surface; Cells; Chemoprevention; Clinical Research; Clinical Trials; Colorectal Cancer; Complex; Data; Development; Disease; Dose; Drug-sensitive; Endothelial Cells; Endothelium; Engineering; Event; Experimental Models; Figs - dietary; Genetic Models; Genetic Transcription; Genotype; Goals; Growth; Growth Factor; Hormone Receptor; Human; Incidence; Indium; Investigation; Knockout Mice; Legitimacy; Link; MEKs; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maps; Measures; Mediating; Minor; Modeling; Molecular; Molecular Target; Monitor; Mus; Neoplasm Metastasis; Oncogenic; Outcome; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Positive Lymph Node; Prevention; Prevention strategy; Preventive; Process; Prognostic Marker; Property; Prostaglandin-Endoperoxide Synthase; Regulation; Reporting; Research Personnel; Research Proposals; Retrospective Studies; Risk; Role; Serum; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Stratification; Subgroup; Surrogate Markers; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Toxic effect; Treatment Efficacy; Treatment outcome; Tumor Angiogenesis; Tumor Cell Invasion; Tumor-Derived; Ubenimex; Validation; Vascular Endothelial Cell; Xenograft procedure; alanine aminopeptidase; angiogenesis; base; cell growth; effective therapy; high risk; improved; infiltrating duct carcinoma; inhibitor/antagonist; malignant breast neoplasm; melanoma; neoplastic; neoplastic cell; neovascularization; neovasculature; new therapeutic target; novel; overexpression; prognostic; programs; promoter; research study; response; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): We have shown that the CD13/APN peptidase is a critical regulator of endothelial cell function and is required for angiogenesis. During endothelial cell activation, CD13/APN expression is induced by tumor-derived growth factors. These signals are transmitted to the nucleus where they enhance the binding of a potentially novel transcription factor to the CD13/APN promoter that is critical for its expression and therefore, its function. Treatment of cells with NSAIDs inhibits the induction of CD13/APN by interfering with the binding of this inducible transcription complex. The fact that NSAIDs directly affect CD13/APN expression suggests that CDI3/APN can serve as a surrogate for NSAIDs-modulated tumor neovascularization and may serve as a marker of treatment efficacy. Because CD 13/APN is also expressed on a subset of breast tumors where we have shown that its expression is regulated as it is in endothelial cells, it is likely that this CD13/APN expression in tumors reflects the dysregulation of normal, NSAIDs-sensitive signaling pathways. Therefore, we propose that NSAIDS treatment will modulate CD13/APN expression in breast tumor cells as well, suggesting that CD13/APN may also be a useful biomarker of NSAIDs prevention in these tumors. We hypothesize that the efficacy of NSAIDS chemoprevention of at-risk breast carcinoma patients can be monitored by assessment of CD13/APN expression either in serum or biopsy specimens. Furthermore, we find that CD13/APN cell surface expression significantly correlates with breast cancer cell invasion and therefore CD13/APN positive breast cancers may comprise a uniquely invasive and NSAIDS-sensitive subgroup. In these tumors we propose that inhibition of CD13/APN expression will inhibit tumor invasion. Finally, NSAIDS functional interference with a novel angiogenesis-induced transcription factor presents a new target for tumor directed therapy. The legitimacy and prognostic potential of predictive biomarkers is dictated by the accuracy and strength of the mechanistic link between a treatment, its specific effect at the site of action, and the desired therapeutic outcome. Therefore, this molecular relationship between chemoprevention, transcriptional modulation, and therapeutic effect warrants further investigation. The experimental plan outlined in this proposal will characterize in detail the features of CD13/APN as an NSAIDS modulatable surrogate marker for the chemoprevention of breast carcinoma, its contribution to tumor invasion and growth, and the molecular mechanisms controlling its regulation.

描述（由申请人提供）：我们已经证明，CD 13/APN肽酶是内皮细胞功能的关键调节因子，是血管生成所必需的。在内皮细胞活化过程中，CD 13/APN表达由肿瘤衍生的生长因子诱导。这些信号被传递到细胞核，在那里它们增强了潜在的新型转录因子与CD 13/APN启动子的结合，这对其表达和功能至关重要。用NSAID处理细胞通过干扰这种诱导型转录复合物的结合来抑制CD 13/APN的诱导。NSAID直接影响CD 13/APN表达的事实表明，CD 13/APN可以作为NSAID调节的肿瘤新血管形成的替代物，并可以作为治疗效果的标志物。由于CD 13/APN也在乳腺肿瘤的一个亚组上表达，我们已经表明其表达与在内皮细胞中一样受到调节，因此肿瘤中的这种CD 13/APN表达可能反映了正常的NSAID敏感性信号传导途径的失调。因此，我们认为NSAIDS治疗也会调节乳腺肿瘤细胞中CD 13/APN的表达，这表明CD 13/APN也可能是NSAIDS预防这些肿瘤的有用生物标志物。我们假设NSAIDS化学预防高危乳腺癌患者的疗效可以通过评估血清或活检标本中CD 13/APN的表达来监测。此外，我们发现CD 13/APN细胞表面表达与乳腺癌细胞侵袭显著相关，因此CD 13/APN阳性乳腺癌可能包含独特的侵袭性和NSAID敏感性亚组。在这些肿瘤中，我们提出抑制CD 13/APN表达将抑制肿瘤侵袭。最后，NSAIDS对新型血管生成诱导转录因子的功能干扰为肿瘤定向治疗提供了新的靶点。预测生物标志物的合法性和预后潜力取决于治疗、其在作用部位的具体效果和期望的治疗结果之间的机械联系的准确性和强度。因此，化学预防、转录调节和治疗效果之间的分子关系值得进一步研究。本提案中概述的实验计划将详细描述CD 13/APN作为乳腺癌化学预防的NSAIDS可调节替代标记物的特征，其对肿瘤侵袭和生长的贡献，以及控制其调节的分子机制。

项目成果

CD13 is dispensable for normal hematopoiesis and myeloid cell functions in the mouse.

• DOI: 10.1189/jlb.0210065
• 发表时间: 2010-08
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Winnicka B;O'Conor C;Schacke W;Vernier K;Grant CL;Fenteany FH;Pereira FE;Liang B;Kaur A;Zhao R;Montrose DC;Rosenberg DW;Aguila HL;Shapiro LH
• 通讯作者: Shapiro LH

CD13 is a novel mediator of monocytic/endothelial cell adhesion.

CD13是单核细胞/内皮细胞粘附的新型介体。

• DOI: 10.1189/jlb.1107802
• 发表时间: 2008-08
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Mina-Osorio P;Winnicka B;O'Conor C;Grant CL;Vogel LK;Rodriguez-Pinto D;Holmes KV;Ortega E;Shapiro LH
• 通讯作者: Shapiro LH