POR overexpression induces tamoxifen-resistance in breast cancer through the STAT1/c-Myc pathway
POR overexpression induces tamoxifen-resistance in breast cancer through the STAT1/c-Myc pathway
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DOI：
10.1002/mc.23481
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发表时间：
2022-11-02
影响因子：
4.6
通讯作者：
Fang, Yue
中科院分区：
文献类型：
--
作者：
Chen, Si;Wu, Dingjie;Fang, Yue
乳腺癌是全世界女性最常见的癌症。尽管选择性雌激素受体(ER)调节剂三苯氧胺()被广泛用于治疗ER阳性乳腺癌，但对的耐药性仍然是一个主要的临床问题。NADPH依赖的细胞色素P450还原酶(POR)参与药物代谢和类固醇代谢。最近的研究表明，在三阴性乳腺癌(TNBC)中，POR的高表达与预后不良相关，POR可能是TNBC的一个预后生物标志物。然而，POR在抵抗中的作用仍不清楚。在这项研究中，我们发现高POR表达与ER阳性和治疗的乳腺癌患者预后不良相关。此外，COX分析显示，POR的表达是ER阳性和治疗的乳腺癌患者的一个独立的预后生物标志物。此外，我们的结果表明，POR的过表达通过激活ER阳性乳腺癌细胞中的STAT1/c-Myc通路而促进了对的抵抗。免疫组织化学分析显示，在治疗的乳腺癌患者中，POR/STAT1的高表达与预后不良相关。值得注意的是，和一种特定的STAT1抑制剂氟达拉滨联合治疗对抑制耐药的乳腺癌细胞更有效。综上所述，我们的研究结果表明，POR过表达通过STAT1/c-Myc通路诱导抵抗，并可能作为治疗的乳腺癌患者的独立预后生物标志物。联合应用和STAT1抑制剂可能是治疗POR诱导的耐药乳腺癌的有效策略。
Breast cancer is the most common cancer in women worldwide. Although tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is widely used to treat ER-positive breast cancers, resistance to TAM remains a major clinical problem. NADPH-dependent cytochrome P450 reductase (POR) is known to participate in drug metabolism and steroid metabolism. Recent studies showed that high POR expression was correlated with poor outcomes in triple-negative breast cancer (TNBC), and POR might be a prognostic biomarker in TNBC. However, the role of POR in TAM resistance is still elusive. In this study, we found that high POR expression was associated with poor prognosis of ER-positive and TAM-treated breast cancer patients. In addition, COX analysis showed that POR expression was an independent prognostic biomarker for ER-positive as well as TAM-treated breast cancer patients. Furthermore, our results suggested that POR overexpression promoted TAM resistance by activating the STAT1/c-Myc pathway in ER-positive breast cancer cells. Immunohistochemical analysis showed that high POR/STAT1 expression was correlated with poor prognosis in TAM-treated breast cancer patients. Notably, combined treatment with TAM and a specific STAT1 inhibitor Fludarabine was more effective for inhibiting TAM-resistant breast cancer cells. Altogether, our findings suggested that POR overexpression induced TAM resistance through STAT1/c-Myc pathway and might serve as an independent prognostic biomarker in TAM-treated breast cancer patients. Combining TAM and STAT1 inhibitors might be an effective strategy for treating POR-induced TAM-resistant breast cancer.