HER2阳性乳腺癌赫赛汀耐药性依然是广泛关注的课题。我们通过高通量基因测序、基因芯片，结合生物信息学筛选出LMO4具有3’UTR缩短特征，在赫赛汀耐药性细胞和肿瘤干细胞中表达上调，根据LMO4被报道的相关功能推测很可能参与肿瘤干细胞和赫赛汀耐药性的调节。我们在BT474细胞体系中初步证明LMO4的3’UTR缩短现象与其在肿瘤干细胞和赫赛汀耐药性细胞中表达上调相关，LMO4能够调控赫赛汀耐药性细胞BT474 HR的药物抗性。在本课题中我们将深入探索LMO4 3’UTR缩短通过逃避miRNA抑制作用调控基因表达的机制；LMO4由于3’UTR缩短导致表达上升调控肿瘤干细胞行为介导赫赛汀耐药性的功能。我们将分别通过细胞实验、小鼠实验以及病人组织分析等进行全面验证。本项目的实施对于探索和完善乳腺癌赫赛汀耐药性的机制具有重要意义，并将为临床诊断和治疗提供新的理论依据，为发展新型乳腺癌治疗药物奠定基础。

Acquired resistance to Herceptin in HER2 positive mammary carcinoma cells remains one big problem. In our study, we did high throughput sequencing in Herceptin resistant mammary carcinoma cells and did microarray in breast cancer stem cells (CSCs). LMO4 was selected as one potential gene to study which has alternative cleavage and polyadenylation (APA) in 3’ untranslated regions (3’UTRs) resulting in 3’UTR shortening, and over-expresses in Herceptin resistant cells and CSCs. According to the feature and functions of LMO4 as previous studies reported, LMO4 may play an important role in Herceptin resistance and breast CSCs. In our study, we confirmed LMO4 increased in BT474 HR (Herceptin resistance) cells and BT474 CSCs with an increased proportion of 3’UTR shortening, and LMO4 mediates Herceptin resistance in BT474 HR cells. For further study, we will explore escaping of the inhibition of miRNAs in LMO4 3’UTR shortening resultes in the increase of the protein level, and LMO4 mediates Herceptin resistance by promoting cancer stem cell-like behavior. We will do experiments both in vitro and in vivo, and will confirm our results in clinical tissues. In this project, we will raise a new mechanism in acquired resistance to Herceptin of HER2 positive mammary carcinoma, and will offer new potential adjuvant therapeutic candidates to enhance trastuzumab efficacy in HER2-positive mammary carcinoma.