Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen
Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen
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DOI：
10.1158/0008-5472.can-20-1705
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Dabrosin, Charlotta
中科院分区：
文献类型：
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作者：
Abrahamsson, Annelie;Rodriguez, Gabriela Vazquez;Dabrosin, Charlotta
虽然阻断雌激素依赖的信号转导是乳腺癌辅助治疗的基石，但25%的患者经历了复发。间质事件，包括先天免疫反应，是癌症进展的关键。不同的雌激素受体(ER)靶向治疗，包括部分激动剂他莫昔芬和纯拮抗剂Fulvestrant，如何影响肿瘤间质尚未阐明。氟维司琼仅用于绝经后患者，其在雌二醇存在下的效果尚不确定。在此，我们观察到，与他莫昔芬相比，在裸鼠体内存在生理水平的雌二醇的人乳腺癌和免疫能力强的小鼠的小鼠乳腺癌中，氟维斯特可以减少ER+乳腺癌的生长。在两种模型中，氟维司琼均能显著抑制巨噬细胞和中性粒细胞的侵袭。这些效应在斑马鱼模型中得到证实，在斑马鱼模型中，弗维斯特比他莫昔芬更有效地抑制依赖中性粒细胞和巨噬细胞的癌细胞扩散。通过体内微透析采样的癌细胞对释放到癌细胞微环境中的234种蛋白质进行了综合分析，结果显示，两种治疗方法都改变了38种蛋白质；其中25种蛋白质与免疫反应有关，仅被富维司琼改变。与他莫昔芬相比，氟维斯特显著影响小鼠基质细胞释放的炎性蛋白。重要的是，对人ER+乳腺癌的体内微透析显示，在小鼠模型中，大多数受影响的蛋白质在患者中上调。综上所述，这些结果表明，富维斯特即使在雌激素存在的情况下，也比他莫昔芬更有效地靶向ER+乳腺癌，主要是通过减弱先天免疫反应。意义：这些发现展示了纯抗雌激素富维斯特治疗ER+乳腺癌的新效果，并评估了其在生理水平下的效果，雌激素是绝经前患者的代表。
Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response.Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.