Department of Molecular and Cellular Biology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2011 Mar 1;71(5):1742-51. doi: 10.1158/0008-5472.CAN-10-3453. Epub 2011 Feb 22.
Metastatic breast cancer remains a lethal disease with poorly understood molecular mechanisms. Steroid receptor coactivator-1 (SRC-1 or NCOA1) is overexpressed in a subset of breast cancers with poor prognosis. It potentiates gene expression by serving as a coactivator for nuclear receptors and other transcription factors. We previously reported that SRC-1 promotes breast cancer metastasis without affecting primary mammary tumor formation. Herein, we found that SRC-1 deficiency in mouse and human breast cancer cells substantially reduced cell adhesion and migration capabilities on fibronectin and significantly extended the time of focal adhesion disassembly and reassembly. In agreement with this phenotype, SRC-1 expression positively correlated with integrin α(5) (ITGA5) expression in estrogen receptor-negative breast tumors whereas SRC-1 deficiency decreased ITGA5 expression. Furthermore, ITGA5 reduction in SRC-1-deficient/insufficient breast cancer cells or knockdown of ITGA5 in SRC-1-expressing breast cancer cells was associated with a disturbed integrin-mediated signaling. Critical downstream changes included reduced phosphorylation and/or dampened activation of focal adhesion kinase, paxillin, Rac1, and Erk1/2 during cell adhesion. Finally, we found that SRC-1 enhanced ITGA5 promoter activity through an AP-1 (activator protein)-binding site proximal to the transcriptional initiation site; both SRC-1 and c-Jun were recruited to this promoter region in breast cancer cells. These results show that SRC-1 can promote breast cancer metastasis by directly enhancing ITGA5 expression and thus promoting ITGA5-mediated cell adhesion and migration. Therefore, targeting ITGA5 in SRC-1-positive breast cancers may result in inhibition of SRC-1-promoted breast cancer metastasis.
转移性乳腺癌仍然是一种致命疾病，其分子机制尚未完全阐明。甾体受体共激活因子-1（SRC-1 或 NCOA1）在预后不良的一部分乳腺癌中过度表达。它通过作为核受体和其他转录因子的共激活因子来增强基因表达。我们之前报道过，SRC-1 促进乳腺癌转移，而不影响原发性乳腺肿瘤的形成。在此，我们发现 SRC-1 在小鼠和人乳腺癌细胞中的缺失显著降低了细胞在纤维连接蛋白上的黏附能力和迁移能力，并显著延长了焦点黏附解离和重新组装的时间。与这种表型一致，SRC-1 在雌激素受体阴性的乳腺癌肿瘤中的表达与整合素 α（5）（ITGA5）的表达呈正相关，而 SRC-1 的缺失降低了 ITGA5 的表达。此外，SRC-1 缺陷/不足的乳腺癌细胞中 ITGA5 的减少或 SRC-1 表达的乳腺癌细胞中 ITGA5 的敲低与整合素介导的信号转导紊乱有关。关键的下游变化包括在细胞黏附过程中，粘着斑激酶、桩蛋白、Rac1 和 Erk1/2 的磷酸化和/或激活减弱。最后，我们发现 SRC-1 通过靠近转录起始位点的 AP-1（激活蛋白）结合位点增强 ITGA5 启动子活性；SRC-1 和 c-Jun 都被招募到乳腺癌细胞中的这个启动子区域。这些结果表明，SRC-1 可以通过直接增强 ITGA5 的表达来促进乳腺癌转移，从而促进 ITGA5 介导的细胞黏附和迁移。因此，在 SRC-1 阳性的乳腺癌中靶向 ITGA5 可能会抑制 SRC-1 促进的乳腺癌转移。
