CD13 as a Biomaker for Chemoprevention of Breast Cancer

描述(由申请人提供)：我们已经证明CD13/APN多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。在内皮细胞激活过程中，CD13/APN的表达是由肿瘤源性生长因子诱导的。这些信号被传递到细胞核，在那里它们增强了一个潜在的新转录因子与CD13/APN启动子的结合，这对CD13/APN的表达和功能至关重要。用NSAIDs处理细胞，通过干扰CD13/APN的诱导转录复合体的结合来抑制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调控的肿瘤新生血管的替代物，并可作为疗效的标志。由于CD13/APN也表达在乳腺肿瘤的一个亚群上，我们已经证明CD13/APN的表达受到内皮细胞的调节，很可能这种CD13/APN在肿瘤中的表达反映了正常的、非类固醇抗炎药敏感的信号通路的失调。因此，我们认为NSAIDs治疗也会调节CD13/APN在乳腺肿瘤细胞中的表达，提示CD13/APN也可能是预防NSAIDs在这些肿瘤中的有用的生物标志物。我们假设，通过评估血清或活检标本中CD13/APN的表达，可以监测非类固醇类药物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著相关，因此CD13/APN阳性乳腺癌可能构成一个独特的侵袭性和非甾体抗炎药敏感的亚群。在这些肿瘤中，我们认为抑制CD13/APN的表达将抑制肿瘤的侵袭。最后，NSAIDs对一种新的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一个新的靶点。预测生物标志物的合法性和预后潜力取决于治疗、作用部位的特定效果和预期治疗结果之间的机制联系的准确性和强度。因此，化学预防、转录调控和治疗效果之间的这种分子关系值得进一步研究。该计划将详细描述CD13/APN作为NSAIDs可调节的乳腺癌化学预防替代标志物的特征，它对肿瘤侵袭和生长的贡献，以及控制其调控的分子机制。

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.