CD13 as a Biomarker for Chemoprevention of Breast Cancer

CD13 作为乳腺癌化学预防的生物标志物

• 批准号: 6875826
• 负责人: LINDA H SHAPIRO
• 金额: $ 29.21万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875826
• 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）：我们已经证明CD13/APN肽酶是内皮细胞功能的关键调节剂并且是血管生成所必需的。在内皮细胞激活期间，CD13/APN 表达由肿瘤源性生长因子诱导。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 CD13/APN 启动子的结合，这对于其表达及其功能至关重要。用 NSAID 处理细胞可通过干扰这种诱导性转录复合物的结合来抑制 CD13/APN 的诱导。 NSAIDs 直接影响 CD13/APN 表达的事实表明，CDI3/APN 可以作为 NSAIDs 调节的肿瘤新生血管形成的替代物，并可以作为治疗效果的标志。由于 CD 13/APN 也在乳腺肿瘤的一个子集中表达，我们已经证明其表达与内皮细胞一样受到调节，因此肿瘤中的 CD13/APN 表达很可能反映了正常的、NSAIDs 敏感的失调。信号通路。因此，我们提出 NSAIDS 治疗也将调节乳腺肿瘤细胞中 CD13/APN 的表达，这表明 CD13/APN 也可能是 NSAIDs 预防这些肿瘤的有用生物标志物。我们假设可以通过评估血清或活检标本中的 CD13/APN 表达来监测 NSAIDS 对高危乳腺癌患者的化学预防效果。此外，我们发现CD13/APN细胞表面表达与乳腺癌细胞侵袭显着相关，因此CD13/APN阳性乳腺癌可能包含独特的侵袭性和NSAIDS敏感亚组。在这些肿瘤中，我们认为抑制 CD13/APN 表达将抑制肿瘤侵袭。最后，非甾体抗炎药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之间机制联系的准确性和强度、作用部位的具体效果以及所需的治疗结果。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 CD13/APN 作为用于乳腺癌化学预防的 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。