Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Breast Cancer Res Treat. 2021 Jan;185(2):281-292. doi: 10.1007/s10549-020-05948-0. Epub 2020 Oct 1.
Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, lacks the three major receptors for predicting outcome or targeting therapy. Hence, our aim was to evaluate the potential of estrogen receptor beta (ERβ) as a possible endocrine therapy target in TNBC.
The expression and prognostic effect of ERβ isoforms were analyzed using TCGA breast tumor data, and the expression of ERβ isoform mRNA and protein in TNBC cell lines was assayed. Endogenous ERβ2 and ERβ5 were knocked down with siRNA, and ERβ2, ERβ5, and ERβ1 were upregulated using a doxycycline-inducible lentiviral system. Cell proliferation, migration and invasion, and specific gene expressions were evaluated.
ERβ2 and ERβ5 were the predominant endogenous forms of ERβ in TNBC tumors and cell lines. High ERβ2 predicted worse clinical outcome. Knockdown of endogenous ERβ2/ERβ5 in cell lines suppressed proliferation, migration and invasion, and downregulated proto-oncogene survivin expression. ERβ2/ERβ5 upregulation did the reverse, increasing survivin and these cell activities. ERβ1 was barely detectable in TNBC cell lines, but its upregulation reduced survivin, increased tumor suppressor expression (E-cadherin and cystatins), and suppressed proliferation, migration and invasion in both ligand-independent and dependent manners, suggesting the possible translational benefit of ERβ ligands.
ERβ2/ERβ5 and ERβ1 exhibit sharply contrasting activities in TNBC cells. Our findings imply that delineating the absolute amounts and relative ratios of the different ERβ isoforms might have prognostic and therapeutic relevance, and could enable better selection of optimal approaches for treatment of this often aggressive form of breast cancer.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，缺乏预测预后或靶向治疗的三种主要受体。因此，我们的目的是评估雌激素受体β（ERβ）作为 TNBC 可能的内分泌治疗靶点的潜力。
使用 TCGA 乳腺肿瘤数据分析 ERβ 异构体的表达和预后影响，并检测 TNBC 细胞系中 ERβ 异构体 mRNA 和蛋白的表达。用 siRNA 敲低内源性 ERβ2 和 ERβ5，用四环素诱导的慢病毒系统上调 ERβ2、ERβ5 和 ERβ1。评估细胞增殖、迁移和侵袭以及特定基因的表达。
ERβ2 和 ERβ5 是 TNBC 肿瘤和细胞系中主要的内源性 ERβ 形式。高 ERβ2 预示着更差的临床结局。细胞系中内源性 ERβ2/ERβ5 的敲低抑制了增殖、迁移和侵袭，并下调了原癌基因 survivin 的表达。ERβ2/ERβ5 的上调则相反，增加了 survivin 和这些细胞活性。TNBC 细胞系中几乎检测不到 ERβ1，但它的上调降低了 survivin，增加了肿瘤抑制因子表达（E-钙黏蛋白和胱抑素），并以配体非依赖性和依赖性方式抑制增殖、迁移和侵袭，表明 ERβ 配体具有潜在的转化益处。
ERβ2/ERβ5 和 ERβ1 在 TNBC 细胞中表现出截然不同的活性。我们的发现表明，明确不同 ERβ 异构体的绝对数量和相对比例可能具有预后和治疗相关性，并能够更好地选择治疗这种侵袭性乳腺癌的最佳方法。
