Abstract：
Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
摘要：
基质衍生因子-1α(SDF-1α)及其同源受体CXCR4在介导乳腺癌细胞侵袭和转移中起关键作用。因此,能够抑制CXCR4激活的药物可能会增加减少肿瘤进展的关键工具，尤其是在最具侵袭性的乳腺癌疾病中。过氧化物酶体增殖物激活受体(PPAR)γ,核受体超家族的成员，已经发现在不同的癌细胞中下调CXCR4基因的表达，然而，这种效应的分子机制尚不完全清楚。这里,我们发现了一种新的PPARγ介导的机制,该机制在上皮和基质乳腺癌细胞中均负调节CXCR4的表达.我们发现，配体激活的PPARγ通过将类视黄醇和甲状腺激素受体（SMRT）的沉默介体募集到乳腺癌细胞系CXCR4启动子内新鉴定的PPAR反应元件（PPRE）上，下调CXCR4的转录活性。因此,PPARγ激动剂罗格列酮(BRL)显著抑制细胞迁移和侵袭,因为它在PPARγ拮抗剂GW9662存在下被逆转。根据癌症相关成纤维细胞（CAFs）的能力，乳腺癌间质中最丰富的成分，分泌高水平的SDF-1α,BRL降低了源自CAF的条件培养基（CM）诱导的迁移促进活性，并影响了CAF-CM激活的CXCR4下游信号通路。此外,暴露于BRL的CAF显示CXCR4的表达降低，运动性和侵袭性降低以及以形态改变为特征的表型。总的来说，我们的研究结果为PPARγ在抑制乳腺癌进展中的作用提供了新的见解,并进一步强调了PPARγ配体在针对乳腺癌患者的癌症和周围基质细胞的未来治疗中的实用性.
