Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):774-9. doi: 10.1073/pnas.1011845108. Epub 2010 Dec 27.
Retinoic acid is a potent differentiation and antiproliferative agent of breast cancer cells, and one of its receptors, retinoic acid receptor β (RARβ), 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 RARβ signature in human microdissected breast tissues that differentiates tumor from normal stroma. Our study thus implicates RARβ in promoting tumorigenesis and suggests that retinoid-based approaches for the prevention and treatment of breast cancer should be redesigned.
视黄酸是乳腺癌细胞强有力的分化和抗增殖剂，其受体之一视黄酸受体β（RARβ）被认为是一种肿瘤抑制因子。相比之下，我们在此报告，在小鼠中敲除 Rarb 会对 ErbB2 诱导的乳腺肿瘤发生产生保护作用。引人注目的是，组织重组实验表明 Rarb 在基质区室中的存在对于乳腺癌的生长是必需的。Rarb 的缺失会导致肿瘤进展过程中基质的重塑，包括血管生成减少、炎性细胞募集减少和肌成纤维细胞数量减少。与这一发现一致，我们观察到 Rarb 缺失小鼠的基质中趋化因子（C-X-C 基序）配体 12（Cxcl12）的表达明显降低，伴随着肿瘤中 CXCL12/趋化因子 C-X-C 受体 4（CXCR4）/ErbB2 信号轴的减少。Rarb 缺失的乳腺基质区室的基因表达谱鉴定出人类微切割乳腺组织中与肿瘤区分开的正常基质的 RARβ 特征，这突出了与人类疾病的相关性。我们的研究因此表明 RARβ 参与促进肿瘤发生，并提示基于类视黄醇的方法用于预防和治疗乳腺癌应该重新设计。
