Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
Am J Pathol. 2012 Apr;180(4):1474-84. doi: 10.1016/j.ajpath.2011.12.032. Epub 2012 Feb 14.
The nuclear receptor coactivator amplified in breast cancer 1 (AIB1/SRC-3) has a well-defined role in steroid and growth factor signaling in cancer and normal epithelial cells. Less is known about its function in stromal cells, although AIB1/SRC-3 is up-regulated in tumor stroma and may, thus, contribute to tumor angiogenesis. Herein, we show that AIB1/SRC-3 depletion from cultured endothelial cells reduces their proliferation and motility in response to growth factors and prevents the formation of intact monolayers with tight junctions and of endothelial tubes. In AIB1/SRC-3(+/-) and (-/-) mice, the angiogenic responses to subcutaneous Matrigel implants was reduced by two-thirds, and exogenously added fibroblast growth factor (FGF) 2 did not overcome this deficiency. Furthermore, AIB1/SRC-3(+/-) and (-/-) mice showed similarly delayed healing of full-thickness excisional skin wounds, indicating that both alleles were required for proper tissue repair. Analysis of this defective wound healing showed reduced recruitment of inflammatory cells and macrophages, cytokine induction, and metalloprotease activity. Skin grafts from animals with different AIB1 genotypes and subsequent wounding of the grafts revealed that the defective healing was attributable to local factors and not to defective bone marrow responses. Indeed, wounds in AIB1(+/-) mice showed reduced expression of FGF10, FGFBP3, FGFR1, FGFR2b, and FGFR3, major local drivers of angiogenesis. We conclude that AIB1/SRC-3 modulates stromal cell responses via cross-talk with the FGF signaling pathway.
乳腺癌扩增的核受体辅激活子 1（AIB1/SRC-3）在癌症和正常上皮细胞中的类固醇和生长因子信号中具有明确的作用。其在基质细胞中的功能知之甚少，尽管 AIB1/SRC-3 在肿瘤基质中上调，可能有助于肿瘤血管生成。在此，我们表明，从培养的内皮细胞中耗尽 AIB1/SRC-3 会降低它们对生长因子的增殖和迁移能力，并防止形成具有紧密连接和完整内皮管的完整单层。在 AIB1/SRC-3(+/-)和(-/-)小鼠中，皮下 Matrigel 植入物的血管生成反应减少了三分之二，并且外源性添加的成纤维细胞生长因子 (FGF) 2 不能克服这种缺陷。此外，AIB1/SRC-3(+/-)和(-/-)小鼠的全层切除皮肤伤口的愈合也表现出类似的延迟，表明两个等位基因都需要正确的组织修复。对这种有缺陷的伤口愈合的分析表明，炎症细胞和巨噬细胞的募集减少，细胞因子诱导和金属蛋白酶活性降低。具有不同 AIB1 基因型的动物的皮肤移植物和随后对移植物的创伤表明，有缺陷的愈合归因于局部因素而不是骨髓反应缺陷。事实上，AIB1(+/-)小鼠的伤口表现出 FGF10、FGFBP3、FGFR1、FGFR2b 和 FGFR3 的表达减少，这些是血管生成的主要局部驱动因素。我们得出结论，AIB1/SRC-3 通过与 FGF 信号通路的串扰调节基质细胞反应。
