The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression
The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression
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DOI：
10.1128/mcb.00579-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Xu, Jianming
中科院分区：
文献类型：
--
作者：
Qin, Li;Liao, Lan;Xu, Jianming
乳腺癌扩增因子1（Amplified-in-breast cancer 1，AIB 1）是乳腺癌中过表达的转录辅激活因子。尽管过度表达的AIB 1是致癌的，但其在转移中的作用和潜在机制仍不清楚。在此，研究了携带小鼠乳腺肿瘤病毒-多瘤病毒中T（PyMT）转基因的野生型（WT）和AIB 1（-/-）小鼠的乳腺肿瘤发生和肺转移。所有WT/PyMT小鼠均发生了大规模肺转移，但具有可比乳腺肿瘤的AIB 1（-/-）/PyMT小鼠的肺转移显著较少。具有移植的AIB 1（-/-）/PyMT肿瘤的受体小鼠的肺转移也比具有移植的WT/PyMT肿瘤的受体小鼠少得多。WT/PyMT肿瘤细胞表达间充质标记物，如波形蛋白和N-钙粘蛋白，迁移和侵袭迅速，并在三维培养中形成混乱的细胞团。相反，AIB 1（-/-）/PyMT肿瘤细胞保持上皮标记物如E-cadherin和ZO-1，迁移和侵袭缓慢，并且在三维培养中仍然形成极化的腺泡结构。分子分析显示，AIB 1作为PEA 3的共激活剂，并与PEA 3在基质金属蛋白酶2（MMP 2）和MMP 9启动子上形成复合物，以增强其在小鼠和人乳腺癌细胞中的表达。在560例人类乳腺肿瘤中，发现AIB 1表达与PEA 3、MMP 2和MMP 9正相关。这些研究结果提出了一种新的替代策略，通过抑制其上游辅助调节因子AIB 1来控制这些MMPs在乳腺癌中的有害作用。
Amplified-in-breast cancer 1 (AIB1) is an overexpressed transcriptional coactivator in breast cancer. Although overproduced AIB1 is oncogenic, its role and underlying mechanisms in metastasis remain unclear. Here, mammary tumorigenesis and lung metastasis were investigated in wild-type (WT) and AIB1(-/-) mice harboring the mouse mammary tumor virus-polyomavirus middle T (PyMT) transgene. All WT/PyMT mice developed massive lung metastasis, but AIB1(-/-)/PyMT mice with comparable mammary tumors had significantly less lung metastasis. The recipient mice with transplanted AIB1(-/-)/PyMT tumors also had much less lung metastasis than the recipient mice with transplanted WT/PyMT tumors. WT/PyMT tumor cells expressed mesenchymal markers such as vimentin and N-cadherin, migrated and invaded rapidly, and formed disorganized cellular masses in three-dimensional cultures. In contrast, AIB1(-/-)/PyMT tumor cells maintained epithelial markers such as E-cadherin and ZO-1, migrated and invaded slowly, and still formed polarized acinar structures in three-dimensional cultures. Molecular analyses revealed that AIB1 served as a PEA3 coactivator and formed complexes with PEA3 on matrix metalloproteinase 2 (MMP2) and MMP9 promoters to enhance their expression in both mouse and human breast cancer cells. In 560 human breast tumors, AIB1 expression was found to be positively associated with PEA3, MMP2, and MMP9. These findings suggest a new alternative strategy for controlling the deleterious roles of these MMPs in breast cancer by inhibiting their upstream coregulator AIB1.