Herceptin对HER2+乳腺癌临床疗效显著,但易发生耐药、且机制尚未完全探明。以往研究发现ERα36能激活乳腺癌中AKT和ERK信号通路，产生内分泌治疗耐药；我们前期结果提示ERα36能激活HER2信号通路。我们假设：ERα36和HER2相互作用，在STAT3分子协同下激活HER2 信号通路，促进HER2+乳腺癌生长及Herceptin耐药。我们将采用细胞及分子生物学技术，以乳腺癌细胞系、裸鼠及临床样本为研究对象：1.明确ERα36能否促进Herceptin耐药；2.研究ERα36激活HER2 信号通路的新机制；3.探索ERα36在STAT3分子协同下促进HER2+乳腺癌干细胞自我更新及Herceptin耐药的机制；4.评价ERα36作为预测HER2+乳腺癌预后及Herceptin耐药的价值。该研究成果将揭示Herceptin耐药的新机制，并为HER2+乳腺癌临床治疗提供新的策略。

Herceptin has significantly improved outcome in HER2-positive breast cancer patients, but is prone to drug resistance. The mechanisms of resistance to Herceptin have not been completely clarified. Previous studies from others found that ER-α36 could activate both AKT and ERK signal pathways, and produced endocrine therapy resistance in breast cancer. Our preliminary results suggested that ER-α36 could activate HER2 signaling pathways. Therefore, we hypothesize that ER-α36 interacts with HER2, then activates HER2 and its down-stream signaling pathways under the coordination of STAT3, to promote the growth of cancer cells and the resistance to Herceptin in HER2-positive breast cancer. For proving the hypothesis above, we will perform all experiments in breast cancer cell lines, nude mice and clinical samples, by utilizing the technologies of cellular and molecular biology. We will focus on four goals in this study. First, we will determine whether ER-α36 promotes resistance to Herceptin. Second, we will study the new mechanisms of HER2 signal pathway activated by ER-α36. Third, we will explore the novel mechanisms of promoting cancer stem cell self-renewal and resistance to Herceptin promoted by ER-α36, under the coordination of STAT3 in HER2-positive breast cancer. Finally, we will evaluate whether ER-α36 could be an excellent predictor of cancer prognosis and resistance to Herceptin in HER2-positive breast cancer. The results expected from this study will define the novel mechanisms of resistance to Herceptin, and provide the novel strategies for clinical managements of HER2-positive breast cancer.