Department of Pathology, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Carcinogenesis. 2010 Dec;31(12):2049-57. doi: 10.1093/carcin/bgq192. Epub 2010 Sep 27.
Tamoxifen is the most commonly prescribed therapy for patients with estrogen receptor (ER)α-positive breast tumors. Tumor resistance to tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress human epidermal growth factor receptor 2 (HER2). Current preclinical models of HER2 overexpression fail to recapitulate the clinical spectrum of endocrine resistance associated with HER2/ER-positive tumors. Here, we show that ectopic expression of a clinically important oncogenic isoform of HER2, HER2Δ16, which is expressed in >30% of ER-positive breast tumors, promotes tamoxifen resistance and estrogen independence of MCF-7 xenografts. MCF-7/HER2Δ16 cells evade tamoxifen through upregulation of BCL-2, whereas mediated suppression of BCL-2 expression or treatment of MCF-7/HER2Δ16 cells with the BCL-2 family pharmacological inhibitor ABT-737 restores tamoxifen sensitivity. Tamoxifen-resistant MCF-7/HER2Δ16 cells upregulate BCL-2 protein levels in response to suppressed ERα signaling mediated by estrogen withdrawal, tamoxifen treatment or fulvestrant treatment. In addition, HER2Δ16 expression results in suppression of BCL-2-targeting microRNAs miR-15a and miR-16. Reintroduction of miR-15a/16 reduced tamoxifen-induced BCL-2 expression and sensitized MCF-7/HER2Δ16 to tamoxifen. Conversely, inhibition of miR-15a/16 in tamoxifen-sensitive cells activated BCL-2 expression and promoted tamoxifen resistance. Our results suggest that HER2Δ16 expression promotes endocrine-resistant HER2/ERα-positive breast tumors and in contrast to wild-type HER2, preclinical models of HER2Δ16 overexpression recapitulate multiple phenotypes of endocrine-resistant human breast tumors. The mechanism of HER2Δ16 therapeutic evasion, involving tamoxifen-induced upregulation of BCL-2 and suppression of miR-15a/16, provides a template for unique therapeutic interventions combining tamoxifen with modulation of microRNAs and/or ABT-737-mediated BCL-2 inhibition and apoptosis.
他莫昔芬是治疗雌激素受体 (ER)α阳性乳腺癌患者最常用的治疗方法。肿瘤对他莫昔芬的耐药性仍然是一个严重的临床问题，特别是在肿瘤也过度表达人表皮生长因子受体 2 (HER2)的患者中。目前的 HER2 过表达的临床前模型未能重现与 HER2/ER 阳性肿瘤相关的内分泌耐药的临床谱。在这里，我们表明，临床上重要的 HER2 致癌异构体 HER2Δ16 的异位表达促进了 MCF-7 异种移植对他莫昔芬的耐药性和雌激素独立性，HER2Δ16 在 >30%的 ER 阳性乳腺癌中表达。MCF-7/HER2Δ16 细胞通过上调 BCL-2 逃避他莫昔芬，而介导的 BCL-2 表达抑制或用 BCL-2 家族药理学抑制剂 ABT-737 处理 MCF-7/HER2Δ16 细胞恢复他莫昔芬敏感性。他莫昔芬耐药的 MCF-7/HER2Δ16 细胞上调 BCL-2 蛋白水平，以响应雌激素耗竭、他莫昔芬治疗或氟维司群治疗介导的 ERα 信号抑制。此外，HER2Δ16 表达导致 BCL-2 靶向 microRNAs miR-15a 和 miR-16 的抑制。miR-15a/16 的再导入降低了他莫昔芬诱导的 BCL-2 表达，并使 MCF-7/HER2Δ16 对他莫昔芬敏感。相反，在他莫昔芬敏感的细胞中抑制 miR-15a/16 激活了 BCL-2 的表达，并促进了他莫昔芬耐药性。我们的结果表明，HER2Δ16 表达促进了内分泌耐药的 HER2/ERα 阳性乳腺癌，与野生型 HER2 不同，HER2Δ16 过表达的临床前模型再现了多种内分泌耐药的人类乳腺癌的表型。HER2Δ16 逃避治疗的机制，涉及他莫昔芬诱导的 BCL-2 上调和 miR-15a/16 的抑制，为结合他莫昔芬与 microRNAs 的调节和/或 ABT-737 介导的 BCL-2 抑制和凋亡的独特治疗干预提供了模板。
