CD13 as a Biomaker for Chemoprevention of Breast ca,

CD13 作为乳腺癌化学预防的生物制造者，

• 批准号: 7069507
• 负责人: LINDA H SHAPIRO
• 金额: $ 28.54万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069507
• 关键词: CD antigens; aminopeptidase; angiogenesis; biomarker; breast neoplasms; cancer prevention; chemoprevention; laboratory mouse; neoplasm /cancer blood supply; neoplastic growth; nonsteroidal antiinflammatory agent; transcription factor; vascular endothelium

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）：我们已经表明，CD13/APN肽酶是内皮细胞功能的关键调节剂，是血管生成所必需的。在内皮细胞活化期间，CD13/APN表达由肿瘤衍生的生长因子诱导。这些信号被传输到核，在那里它们增强了潜在的新型转录因子与CD13/APN启动子的结合，该转录因子对其表达至关重要，因此是其功能。用NSAIDs处理细胞通过干扰该诱导转录复合物的结合来抑制CD13/APN的诱导。 NSAID直接影响CD13/APN表达的事实表明，CDI3/APN可以用作NSAIDS调节的肿瘤新血管形成的替代物，并且可以作为治疗功效的标志。由于CD 13/APN也在乳腺肿瘤的一部分上表达，在该子集中我们表明其表达受到内皮细胞的调节，因此肿瘤中的CD13/APN表达很可能反映了正常的NSAIDS敏感信号通路的失调。因此，我们建议NSAIDS治疗也将在乳腺肿瘤细胞中调节CD13/APN的表达，这表明CD13/APN也可能是预防NSAIDS预防的有用生物标志物。我们假设NSAIDS在血清或活检标本中评估CD13/APN表达的NSAIDS化学预防化学预防疗法可以监测。此外，我们发现CD13/APN细胞表面表达与乳腺癌细胞的侵袭显着相关，因此CD13/APN阳性乳腺癌可能包括独特的入侵性和NSAIDS敏感的亚组。在这些肿瘤中，我们建议抑制CD13/APN表达会抑制肿瘤侵袭。最后，NSAID对新型血管生成诱导的转录因子的功能干扰提出了肿瘤定向治疗的新靶标。预测生物标志物的合法性和预后潜力取决于治疗之间的机械联系的准确性和强度，其在作用部位的特定作用以及所需的治疗结果。因此，化学预防，转录调节和治疗效应之间的这种分子关系值得进一步研究。该提案中概述的实验计划将详细介绍CD13/APN的特征，是NSAIDS可调节的替代标记物，用于乳腺癌的化学预防，其对肿瘤侵袭和生长的贡献以及控制其调节的分子机制。