HER2阳性乳腺癌恶性程度高、患者预后差，存在曲妥珠单抗治疗耐药，这与截断型HER2蛋白表达有密切联系，其中p110-HER2激酶活性最强。前期工作发现，p110-HER2可诱导人乳腺上皮细胞迁移、侵袭、成瘤能力显著增强，故存在强烈癌基因驱动作用。目前认为其生成机制为HER2 mRNA的的选择性翻译起始，但该机制如何启动仍为未知；前期工作亦发现，p110-HER2对应mRNA序列启动子之前存在IRES活性，可能在应激条件下启动HER2 mRNA选择性翻译起始从而产生p110-HER2。本研究拟1)筛选HER2 IRES启动选择性蛋白质翻译的条件；2)验证HER2 IRES介导翻译与p110-HER2产生之间的关系；3)明确HER2 IRES的二级结构和调控ITAF。为进一步理解HER2阳性乳腺癌生物学行为和靶向药物治疗耐药提供新的理论依据。

HER2 positive breast cancer is biologically aggressive, which compromises patients’ prognosis. Trastuzumab resistance is common in HER2 positive breast cancer and related to truncated HER2 generation. Three forms of truncated HER2 were identified, in which, p110-HER2 is the most active isoform. Our previous study showed that p110-HER2 could significantly induce migration, invasion and tumorigenesis in human mammary epithelial cells, which indicating strong oncogenic driver function. Recently, it has been proved that p110-HER2 was generated through alternative initiation of translation, but in which context this mechanism would be triggered is still unknown. Our prior experiments also found that there is IRES activity in HER2 mRNA before p110-HER2 start codon, which could initiate IRES-mediated alternative translation and lead to p110-HER2 generation. Therefore, this project is meant to identify which stress condition could stably induce HER2 IRES activity at a profound level; to prove the relationship between HER2 IRES-mediated translation and p110-HER2 generation under stress condition; to predict and map secondary structure of HER2 IRES as well as to verify HER2 IRES-binding proteins as ITAF, in order to provide more scientific evidences in terms of trastuzumab resistance in HER2 positive breast cancer and novel targeted drug development.