他莫昔芬（TAM）是治疗激素受体阳性乳腺癌的标准内分泌治疗药。TAM耐药是降低其疗效的主因。课题组前期发现NADPH-细胞色素P450还原酶（POR）过表达可致TAM耐药，低表达可提高TAM敏感性，且POR高表达与乳腺癌TAM治疗预后不良相关，提示POR是导致TAM耐药的关键，但其机制尚不清楚。课题组还发现TAM与POR结合；POR表达影响FAM3A二聚体和单体的表达量，且POR与FAM3A结合；理论预测POR与FAM3A及PFK-L形成三体复合物。基于一系列前期结果，课题组提出假说：TAM与POR靶向结合后，使其活性增强，POR进一步与FAM3A二聚体结合后促使其解聚成单体，并招募PFK-L形成三体复合物，促进糖酵解，进而启动肿瘤细胞异常增殖，介导TAM耐药。本项目旨在阐明POR通过上述机制介导TAM耐药，为提高TAM临床治疗疗效及改善预后并制定乳腺癌治疗新策略提供重要理论依据。

Tamoxifen is one of the most successful endocrine therapy drugs for estrogen receptor (ER)-positive breast cancer. Tamoxifen resistance is still a main problem for the treatment of breast cancer, and predictive biomarkers are still elusive. In an attempt to uncover novel moleculars that mediate cellular resistance to tamoxifen, we have found that overexpression of NADPH-cytochrome p450 reductase (POR) causes tamoxifen resistance, while knockdown of POR increases tamoxifen sensitivity. In addition, we have found that POR expression is high in breast cancer and the high POR expression is associated with poor outcomes for patients treated with tamoxifen. Our results suggest that POR is a crux for tamoxifen resistance, but the underlying mechanism remains unclear. Furthermore, we have found that tamoxifen is found to bind to POR. Overexpression of POR increased the expression of FAM3A monomer, but decreased the expression of FAM3A dimer. Moreover, we have found that POR binds FAM3A directly, and POR and FAM3A are predicted to bind to PFK-L directly by using software MOE 2018.0101. Combined with previous studies and our results, we assume that POR is a target of tamoxifen, and binds to tamoxifen directly, resulting in increased activity of POR; additionally, overexpression of POR promoting FAM3A dimer-monomer exchange, and recruiting phosphofructokinase L (PFK-L), thereby activating glycosis. Enhanced glycosis results in abnormal proliferation of breast cancer cells, and leads to tamoxfien resistance. We propose to elucidate a novel resistance mechanism of tamoxifen on breast cancer via POR in this study. We believe that our studies will not only identify a novel useful biomarker of tamoxifen response, but also provide important information for improving therapeutic effects of breast cancer.