Stromal retinoic acid receptor β promotes mammary gland tumorigenesis
Stromal retinoic acid receptor β promotes mammary gland tumorigenesis
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DOI：
10.1073/pnas.1011845108
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发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Giguere, Vincent
中科院分区：
文献类型：
--
作者：
Liu, Xingxing;Nugoli, Melanie;Giguere, Vincent
视黄酸是一种有效的乳腺癌细胞分化和抗增殖剂，其受体之一视黄酸受体β（RAR β）已被提出作为肿瘤抑制剂。与此相反，我们在此报告，在小鼠中的Rarb的失活结果对ErbB 2诱导的乳腺肿瘤发生的保护作用。引人注目的是，组织重组实验表明，Rarb在间质区室的存在是必不可少的乳腺癌的生长。Rarb的消融导致肿瘤进展期间基质的重塑，包括血管生成、炎性细胞募集和肌成纤维细胞数量的减少。与这一发现一致，我们观察到Rarb基因敲除小鼠间质中趋化因子（C-X-C基序）配体12（Cxcl 12）的表达显著降低，伴随着肿瘤中CXCL 12/趋化因子C-X-C受体4（CXCR 4）/ErbB 2信号传导轴的减少。与人类疾病的相关性通过以下发现强调：Rar缺陷型乳腺间质区室的基因表达谱鉴定了人类显微切割的乳腺组织中的直系同源物RAR β特征，其将肿瘤与正常间质区分开。因此，我们的研究暗示RAR β促进肿瘤发生，并建议应重新设计基于维甲酸的预防和治疗乳腺癌的方法。
Retinoic acid is a potent differentiation and antiproliferative agent of breast cancer cells, and one of its receptors, retinoic acid receptor beta (RAR beta), has been proposed to act as a tumor suppressor. In contrast, we report herein that inactivation of Rarb in the mouse results in a protective effect against ErbB2-induced mammary gland tumorigenesis. Strikingly, tissue recombination experiments indicate that the presence of Rarb in the stromal compartment is essential for the growth of mammary carcinoma. Ablation of Rarb leads to a remodeling of the stroma during tumor progression that includes a decrease in angiogenesis, in the recruitment of inflammatory cells, and in the number myofibroblasts. In agreement with this finding, we observed that a markedly reduced expression of chemokine (C-X-C motif) ligand 12 (Cxcl12) in the stroma of Rarb-null mice is accompanied by a decrease in the CXCL12/chemokine C-X-C receptor 4 (CXCR4)/ErbB2 signaling axis in the tumors. Relevance to the human disease is underlined by the finding that gene-expression profiling of the Rarb-deficient mammary stromal compartment identified an ortholog RAR beta signature in human microdissected breast tissues that differentiates tumor from normal stroma. Our study thus implicates RAR beta in promoting tumorigenesis and suggests that retinoid-based approaches for the prevention and treatment of breast cancer should be redesigned.