乳腺癌化疗耐药一直是限制其临床治疗效果的主要瓶颈，而乳腺癌干细胞则是造成乳腺癌耐药、复发转移的罪魁祸首。申请者在对课题组前期建立的具有乳腺癌干细胞样表型的乳腺癌多药耐药细胞系（MCF-7/5-Fu）研究发现：转录因子FOXO3a在耐药细胞中显著高表达且主要定位于细胞核，干扰FOXO3a可增强耐药细胞对化疗药物的敏感性。进一步实验显示，FOXO3a高表达与乳腺癌干细胞样特性相关。据此，我们提出FOXO3a促进肿瘤恶性生物学行为的新机制，即FOXO3a通过促进肿瘤干细胞样特性增强乳腺癌化疗耐药作用。本项目拟在前期工作基础上，通过多个层面解析FOXO3a促进乳腺癌干细胞样特性的内在机制，阐明此过程中的核心环节及关键分子/信号；揭示FOXO3a在乳腺癌耐药细胞及乳腺癌干细胞中异常表达的分子机制；结合乳腺癌临床标本分析，探求并评价FOXO3a作为乳腺癌化疗耐药、复发标志物的有效性和可行性。

Chemotherapy resistant is a major obstacle to the effective treatment of breast cancer, while breast cancer stem cells play a pivotal role in chemotherapy resistance, tumour regeneration and metastasis. We have previously established a 5-Fu-resistant human breast cancer cell line MCF7/5-Fu with cancer stem cell phenotype. We found that FOXO3a transcription factor was significantly increased in 5-Fu-resistance cells, and interference of FOXO3a enhanced the sensitivity of cells to chemotherapeutic agents. Further studies showed that FOXO3a is correlation with breast cancer stem cell-like properties. Therefore, we propose that FOXO3a can enhance chemotherapy resistant in breast cancer via promoting cancer stem cell-like properties, a novel mechanism of FOXO3a in biological behavior of malignant tumors. Accordingly, the major objectives of this research are to evaluate the effects and mechanisms of FOXO3a regulates the breast cancer stem cell-like properties, clarify the central link and key molecule/signal in this process; and reveal the molecular mechanisms of abnormal expression of FOXO3a in breast cancer resistant cells and breast cancer stem-like cells; and then in combination with analysis of breast tumor tissue samples, assess the validity and feasibility for regarding FOXO3a as the molecular marker of breast chemotherapy resistance, tumor regeneration.