Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer.
Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer.
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DOI：
10.1158/0008-5472.can-16-3152
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Cano A
中科院分区：
文献类型：
--
作者：
Salvador F;Martin A;López-Menéndez C;Moreno-Bueno G;Santos V;Vázquez-Naharro A;Santamaria PG;Morales S;Dubus PR;Muinelo-Romay L;López-López R;Tung JC;Weaver VM;Portillo F;Cano A
赖氨酸氧化酶样蛋白LOXL2被认为有助于肿瘤的进展和转移，但缺乏体内证据。本研究提供了功能性证据，证明LOXL2在两种条件转基因小鼠pymt诱导乳腺癌模型中是乳腺癌转移的关键驱动因素。乳腺肿瘤细胞LOXL2消融可显著降低肺转移，而LOXL2过表达可促进转移性肿瘤生长。肿瘤细胞中LOXL2的缺失或过表达不会影响原发性和转移性肿瘤的细胞外基质硬度或组织，这意味着LOXL2的功能独立于其在细胞外基质重塑中的传统作用。为了支持这种可能性，细胞和分子分析显示LOXL2的作用与EMT调节转录因子Snail1水平升高和几种促进转移前生态位形成的细胞因子表达有关。综上所述，我们的研究结果确定了LOXL2在乳腺癌转移中的病理生理作用和新功能。
The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote pre-metastatic niche formation. Taken together, our findings established a pathophysiological role and new function for LOXL2 in breast cancer metastasis.