他莫昔芬耐药乳腺癌来源的精氨酸促进肿瘤相关巨噬细胞激活的研究

他莫昔芬是ERα阳性乳腺癌病人主要的内分泌治疗药物，大约有40%的患者会产生他莫昔芬耐药。他莫昔芬耐药导致的复发转移已成为ERα阳性乳腺癌临床治疗亟待解决的难题。大量研究证实肿瘤相关巨噬细胞（TAMs）在肿瘤细胞的侵袭转移中发挥了重要促进作用，精氨酸代谢通路激活是TAMs激活的重要特征。本课题在预实验中发现他莫昔芬耐受的乳腺癌病人组织有大量M2型TAMs浸润，同时发现他莫昔芬耐药乳腺癌具有较强精氨酸合成能力，而其精氨酸降解能力极弱。基于此，本项目提出以下科学问题，即他莫昔芬耐药乳腺癌来源的精氨酸是否通过促进TAMs的精氨酸代谢促进他莫昔芬耐药乳腺癌的复发转移。本课题将通过基因敲除手段以及分子示踪法在分子水平上证实肿瘤细胞合成的精氨酸促进了TAMs的免疫抑制功能。本课题的成功开展将首次从精氨酸代谢角度揭示M2型TAMs促肿瘤免疫逃逸的分子机制，为他莫昔芬耐药乳腺癌的治疗提供新靶点。

Tamoxifen resistance is accountable for relapse in many ER positive breast cancer patients. It is well established that tumor-associated Macrophages（TAMs）often display an alternatively activated phenotype(M2 TAMs), promoting tumor invasion and metastasis, and arginine metabolism is very important for TAMs to perform pro-tumor functions. In this study, we found that TAMs is very abundant in tamoxifen resistant breast cancer tissues, and tamoxifen resistant breast cancer cell obtained strong arginine synthesis ability, oppositely the arginine degradation ability is very weak. So, we hypothesized that weather tamoxifen resistant breast cancer derived arginine promote the TAMs M2 functional polarization. We confirm the hypothesis by using gene-knockdown and molecular tracing methods, and the success of this study will reveal new molecular mechanisms of metastasis and provide new molecular targets for the treatment of tamoxifen resistant breast cancer patients.