自噬贯穿于肿瘤演进过程中。ULK1是自噬途径的核心蛋白，但其在乳腺癌中的表达和意义尙不清楚。我们研究发现ULK1在乳腺癌细胞株及癌组织中低表达，随着乳腺癌的演进其表达呈逐渐减少的趋势，是一个独立的预后因素；甲基化抑制剂处理后的乳腺癌细胞其ULK1 mRNA表达增高；而过表达ULK1减弱MDA-MB-231细胞的侵袭能力及体内成瘤能力。本课题拟深入研究乳腺癌演进中ULK1启动子区CpG岛的异常甲基化与其低表达的关系；研究ULK1对乳腺癌细胞的基因组稳定性、增殖、成瘤及侵袭转移能力的影响，在体外三维培养模型下研究干扰ULK1对MCF-10A的恶性转化作用；探讨ULK1通过调控自噬及其它新的生物学通路影响乳腺癌恶性进展的分子机制；阐明过表达ULK1能否增强乳腺癌细胞对化疗的敏感性。本研究有助于深入理解自噬在乳腺癌中的作用，为乳腺癌的分子诊断、预后评估等提供新的分子平台，并为乳腺癌的治疗提供新思路

Autophagy is a catabolic process that widely involves in the whole process of human cancers.ULK1 is the furthest upstream kinase involved in autophagosome formation. However, the function and expression of ULK1 in human breast cancer is still scarcely explored. In our prelimilary study, we found that the mRNA and protein levels of ULK1 decreased in breast cancer cells and fresh breast carcinoma tissues, compared with the immortalized breast epithelial cell line (MCF-10A) and matched normal tissues. Gradual decreased expression of ULK1 was associated with breast cancer progression from ductal hyperplasia (DH), to atypical ductal hyperplasia (ADH), and then to ductal carcinoma in situ (DCIS), and finally to invasive ductal carcinomas (IDC). As patients with lower level of ULK1 had higher metastatic potential and poorer prognosis, ULK1 might be used as a novel prognostic biomarker for breast cancer patients. We also found that the mRNA level of ULK1 increased obviously in breast cancer cells after treatment with 5-aza-2'-deoxycytidine. Additionally, overexpression ULK1 inhibited MDA-MB-231 cells invasive ability and suppressed MDA-MB-231 xenograft tumor growth. In this proposal, we further extend our research to detect the aberrent CpG island methylation in promoter region of ULK1 gene , and demonstrate the effect of ULK1 on the breast cancer cells genomic instability, proliferation , the ability to form mice xenograft, invasion and migration of breast cancer cells, and the carcinogenesis transformation of MCF-10A under 3-D culture in vitro. We will also explore the molecular mechanisms of ULK1 affecting breast tumorigenesis through regulation of autophagy and other new signaling pathways, and clarify the significance of over-expressing of ULK1 to breast cancer therapy. The study will provide a comprehensive understanding of relationship between autophagy and breast cancer, introduce a new molecular platform for molecular diagnosis , prognostic evaluation, of breast cancer, and reveal a new valuable pathway for breast cancer therapy.