Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer.
Tumor cell-produced matrix metalloproteinase 9 (MMP-9) drives malignant progression and metastasis of basal-like triple negative breast cancer.
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DOI：
10.18632/oncotarget.1932
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Radisky ES
中科院分区：
文献类型：
--
作者：
Mehner C;Hockla A;Miller E;Ran S;Radisky DC;Radisky ES
基质金属蛋白酶（MMPs）在乳腺癌的发生和发展中起着不同的作用。虽然乳腺癌中表达的许多不同MMP是由基质细胞产生的，但MMP-9主要由肿瘤细胞本身产生。迄今为止，肿瘤细胞产生的MMP-9的功能作用仍不清楚。在这里，我们表明，人乳腺癌细胞产生的MMP-9是特别需要在细胞培养中的入侵和肺转移的基底样乳腺癌小鼠原位模型。我们还发现，肿瘤细胞产生的MMP-9促进肿瘤血管化，对原发性肿瘤生长只有适度的影响，并且MMP-9在肿瘤细胞中表达的沉默导致改变的转录程序，这与恶性程度较低的表型的逆转一致。MMP-9在人基底细胞样和三阴性肿瘤中表达最高，我们的数据表明它有助于转移进展。我们的研究结果表明，MMP 9可能为基底样三阴性乳腺癌的抗转移治疗提供靶点，这是一种预后不良的亚型，几乎没有可用的分子靶向治疗选择。
Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.
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