乳腺癌是威胁女性健康的重大疾病，位居全球女性癌发率首位。高度的肿瘤异质性及与其紧密相关的耐药性是乳腺癌临床诊治面临的巨大挑战。在分子机制水平理解乳腺癌异质性可为其临床诊治提供重要指导。在乳腺癌发展过程，多胺具有重要作用。研究发现靶向多胺代谢网络对乳腺癌治疗具有积极作用，但具体机制有待阐明。申请人近年来在多胺代谢网络方面开展了系列研究，并发现其关键信号轴ODC-OAZ1-AZIN1在肿瘤中被非均衡地调控。通过分析前人研究进展，结合本课题组的发现，本项目提出一个新的科学假设：ODC-OAZ1-AZIN1信号轴非均衡调控与乳腺癌异质性存在特定内在关系，可以通过干预ODC-OAZ1-AZIN1信号轴的非均衡调控来提高乳腺癌细胞对药物的敏感性。本项目相关的前期研究初步验证了该假设的可行性，我们将综合利用信息、分子、细胞、临床等多学科技术在这方面开展深入研究，以期为乳腺癌诊治提供新的角度和理论支持。

Breast cancer is one of the biggest threats to the health of women and has the highest incidence rate in female cancers around the world. Studies found that breast cancer has extremely high inter-tumoral and intra-tumoral heterogeneity, which might be the main cause of the drug resistance of breast cancer in clinic. Therefore, elucidating the molecular mechanism of the tumor heterogeneity would be of great value to the clinical diagnosis and treatment of breast cancer. During the development of breast cancer, polyamines play important roles. A lot studies have shown that targeting the polyamine metabolism network helps inhibiting the growth of breast cancer cells, but there are many controversial findings in this aspect. Recently, the applicant of this project has undertaken a lot work on the polyamine metabolism network, and revealed the fact that the ODC-OAZ1-AZIN1 signaling axis of the polyamine metabolism network is re-configured in an unbalanced manner in tumors. After carefully analyzing the previous studies in this field and based upon the applicant’s findings, the applicant proposed a new scientific hypothesis in this project: There exists a correlation between the unbalanced regulation manners of the ODC-OAZ1-AZIN1 signaling axis and the heterogeneous subtypes of breast cancer, and selectively perturbing the ODC-OAZ1-AZIN1 axis will improve the drug sensitivity and even reverse the drug resistance of breast cancers. Our preliminary results have shown that this hypothesis could be true. Therefore, we will combine the tools from bioinformatics, molecular biology, cellular biology, and clinical analysis to systematically verify this hypothesis. We hope the fruits from this project would provide novel visions and scientific supports for the clinical diagnosis and treatment of breast cancer.