乳腺癌祖细胞调控肿瘤微环境在内分泌治疗耐药中的作用及其机制研究

About 60-70% of breast cancers are estrogen receptor positive and most of them are sensitive to endocrine therapy using Tamoxifen. However, one third of these patients will eventually develop resistance and relapse. Numerous studies indicate that cancer stem/progenitor cells play an important role in resistance to chemotherapy and radiation therapy and have stronger ability to modulate tumor microenvironment. However, whether cancer stem/progenitor cells contribute to endocrine resistance remains unknown. Our preliminary results show that breast cancer progenitor cells are key to Tamoxifen resistance and their expression of microenviroment-associated cytokines are significantly upregulated, suggesting that tumor microenvironment may contribute to Tamoxifen resistance. In this study, we will isolate cancer cells and other mesenchymal cells in tumor microenviroment from fresh breast cancer samples that are either sensitive or resistant to Tamoxifen. The cancer cells and mesenchymal cells will be co-cultured to test their interaction on the effect of Tamoxifen. We will look for the cytokines and signaling pathways that are essential for Tamoxifen resistance. We will also test whether Tamoxifen resistance can be reversed by blocking relevant pathways. The proposed research will elucidate the role of tumor microenviroment in Tamoxifen resistance and provide new therapeutic targets in overcoming Tamoxifen resistance.

雌激素受体（ER）阳性的乳腺癌占全部乳腺癌的60-70%，虽然这类乳腺癌大多对以他莫西芬为主的内分泌治疗敏感，但仍有三分之一左右的患者会产生耐药并复发。肿瘤干/祖细胞在抵抗化疗和放疗中发挥重要作用，且其调控肿瘤微环境的能力更强，但其与乳腺癌内分泌治疗耐药是否有关尚不清楚。我们的研究结果显示乳腺癌祖细胞在他莫西芬耐药中起着重要作用，且其与肿瘤微环境相关的细胞因子表达也明显增高，提示他莫昔芬耐药与肿瘤微环境有关。本研究拟从对他莫西芬敏感或耐药的原发乳腺癌临床标本中分离肿瘤细胞和微环境细胞，通过共培养，研究其相互作用对他莫西芬疗效的影响，明确肿瘤微环境在他莫西芬耐药中的作用，找到其中关键的细胞因子和细胞通路，并测试阻断相关通路是否可减少或逆转耐药，为解决他莫昔芬耐药这个临床难题提供新的治疗靶点。

乳腺癌是最常见的恶性肿瘤，雌激素受体（ER）阳性的乳腺癌占全部乳腺癌的60-70%，虽然这类乳腺癌大多对以他莫西芬为代表的内分泌治疗敏感，但仍有三分之一左右的患者会产生耐药而复发。为了研究内分泌耐药，项目负责人团队从乳腺肿瘤细胞和微环境两方面开展了以下工作：1.乳腺癌祖细胞在他莫昔芬耐药中的作用及机制； 2. LncRNA DILA1抑制CyclinD1的泛素化降解促进ER+乳腺癌的内分泌耐药;3.他莫昔芬耐药乳腺癌细胞中BARD1/BRCA1高表达提示放化疗耐药;4. HDAC10高表达增加乳腺癌他莫昔芬耐药细胞对西达本胺敏感性; 5.巨噬细胞ADCP作用引起乳腺癌的免疫抑制；6.乳腺癌内分泌耐药肿瘤微环境中间质细胞表型变化；7.肿瘤相关巨噬细胞特征基因谱预测乳腺癌预后。根据以上研究成果，负责人团队设计并展开了相关临床研究，有望提高乳腺癌患者的治愈率和生存率。