Estrogenic regulation of host immunity against an estrogen receptor - Negative human breast cancer
Estrogenic regulation of host immunity against an estrogen receptor - Negative human breast cancer
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DOI：
10.1158/1078-0432.ccr-05-1117
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发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Estes, D. Mark
中科院分区：
文献类型：
--
作者：
Curran, Edward M.;Judy, Barbara M.;Estes, D. Mark
目的：患乳腺癌的风险与雌激素暴露水平升高和/或雌激素暴露时间延长呈正相关。人们提出了许多不同的机制来解释雌激素与乳腺癌风险之间的关系；然而，充分证明的雌激素的免疫调节特性却很少受到重视。在某种程度上，这是由于缺乏研究这种关系的合适模型。实验设计：我们建立了一种动物模型，将雌激素受体（ER）阴性的人乳腺癌细胞系MDA-MB-468移植到严重联合免疫缺陷（SCID）小鼠体内。我们还在SCID背景下培育了er - α敲除（er - α KO）小鼠，然后在野生型和er - α KO SCID小鼠中测试了17 - β -雌二醇刺激异种移植er -阴性人乳腺癌肿瘤生长的能力。我们量化了肿瘤的血管化、免疫细胞化学向肿瘤部位募集的巨噬细胞和炎症细胞因子的产生。结果：我们发现雌激素处理C57BL/6/SCID小鼠促进了野生型小鼠异种移植er阴性肿瘤的生长，而雌激素诱导的er α KO小鼠肿瘤生长被消除。雌激素处理小鼠的肿瘤新生血管与对照组相比没有变化；然而，雌激素对C57BL/6/SCID宿主的治疗抑制了巨噬细胞向肿瘤部位的募集和炎症细胞因子的产生。结论：这些数据与雌激素调节炎症反应是雌激素刺激er阴性肿瘤生长的一个促进因素是一致的。这种对宿主先天免疫反应的影响是由er - α介导的。
Purpose: The risk of developing breast cancer is positively correlated with exposure to increased levels of estrogen and/or an increased duration of estrogen exposure. Many different mechanisms have been proposed to explain the association of estrogens with breast cancer risk; however, the well-documented immune modulatory properties of estrogen have received little attention. In part, this is due to a lack of suitable models for studying this relationship.Experimental Design: We have developed an animal model using estrogen receptor (ER)negative human breast cancer cell line, MDA-MB-468, xenografted into severe combined immunodeficient (SCID) mice. We also generated the ER-alpha knockout (ER-alpha KO) mice on the SCID background and then tested the ability of 17 beta-estradiol to stimulate growth of xenografted ER-negative human breast cancer tumors in wild-type and ER-alpha KO SCID mice. We quantified vascularization of tumors, macrophage recruitment to the tumor site by immunocytochemistry, and inflammatory cytokine production.Results: We show that estrogen treatment of C57BL/6/SCID mice promotes the growth of xenografted ER-negative tumors in wild-type mice and this estrogen-induced tumor growth is abrogated in ER-alpha KO mice. Tumor neovascularization of estrogen-treated mice was unchanged versus control; however, estrogen treatment of the C57BL/6/SCID host suppressed macrophage recruitment to and inflammatory cytokine production at the tumor site.Conclusions: These data are consistent with estrogen modulation of the inflammatory response as a contributing factor in estrogen-stimulated growth of an ER-negative tumor. This effect on the host innate immune response was mediated by ER-alpha.