Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients, ~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knock-out cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients.
弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤亚型。尽管联合免疫化疗方案（R-CHOP）已被证实对多数患者有效，但约40%的DLBCL患者会出现治疗无效或复发，因而预后极差。靶向治疗的发展并未改善患者生存，这凸显了对新治疗策略的迫切需求。通过对1800多名DLBCL患者进行全基因组CD20关联分析，我们此前已鉴定出雌激素受体β（ERβ）作为DLBCL的新治疗靶点。本研究显示，与正常B细胞相比，ERβ在DLBCL中表达水平显著升高，且其具有抗凋亡保护作用。使用选择性雌激素受体调节剂他莫昔芬靶向ERβ，可在所有测试的DLBCL细胞系中降低细胞活性。在ERβ敲除的细胞系中，他莫昔芬诱导的细胞死亡显著减少。他莫昔芬的活性在人类淋巴瘤异种移植模型中得以证实，表现为肿瘤生长受抑且生存率显著提升。最后，与未接受他莫昔芬治疗的乳腺癌患者相比，接受他莫昔芬治疗的乳腺癌患者罹患DLBCL的风险降低38%。我们的研究为在他莫昔芬——这一安全性良好的激素药物——在DLBCL患者中的应用研究提供了理论依据。
肿瘤(癌症)患者之家