An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer.
An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer.
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DOI：
10.1007/s10549-012-2220-4
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发表时间：
2012-10
影响因子：
3.8
通讯作者：
Zolkiewska A
中科院分区：
文献类型：
--
作者：
Li H;Duhachek-Muggy S;Qi Y;Hong Y;Behbod F;Zolkiewska A
在没有HER 2过表达的情况下，三阴性乳腺癌（TNBC）依赖于表皮生长因子受体（EGFR/ErbB 1/HER 1）的信号传导来传递生长信号并刺激细胞增殖。可溶性EGF样配体通过ADAM蛋白酶衍生自其跨膜前体，但主要负责TNBC中EGFR的配体释放和活化的ADAM的身份尚不清楚。使用公开的淋巴结阴性乳腺肿瘤患者未接受全身治疗的基因表达数据，我们表明，ADAM 12 L是唯一的ADAM，其表达水平与减少的无远处转移生存时间显著相关。在ER阴性非TNBC患者中未观察到类似效果。ADAM 12 L与HB-EGF、EGFR在TNBC中呈正相关，而在ER阴性的非TNBC中无相关性。我们进一步证明，异位表达的ADAM 12 L增加EGFR的磷酸化在小鼠导管内异种移植模型的早期乳腺癌。最后，我们使用组织微阵列检测人类乳腺肿瘤中抗ADAM 12 L和抗磷酸化EGFR免疫染色水平之间的强相关性。这些研究表明，ADAM 12 L是负责早期淋巴结阴性TNBC中EGFR激活的主要蛋白酶。因此，我们的研究结果可能为TNBC的生物学提供新的见解。
In the absence of HER2 overexpression, triple-negative breast cancers (TNBCs) rely on signaling by epidermal growth factor receptor (EGFR/ErbB1/HER1) to convey growth signals and stimulate cell proliferation. Soluble EGF-like ligands are derived from their transmembrane precursors by ADAM proteases, but the identity of the ADAM that is primarily responsible for ligand release and activation of EGFR in TNBCs is not clear. Using publicly available gene expression data for patients with lymph node-negative breast tumors who did not receive systemic treatment, we show that ADAM12L is the only ADAM whose expression level is significantly associated with decreased distant metastasis-free survival times. Similar effect was not observed for patients with ER-negative non-TNBCs. There was a positive correlation between ADAM12L and HB-EGF and EGFR in TNBCs, but not in ER-negative non-TNBCs. We further demonstrate that ectopic expression of ADAM12L increased EGFR phosphorylation in a mouse intraductal xenograft model of early breast cancer. Finally, we detect strong correlation between the level of anti-ADAM12L and anti-phospho-EGFR immunostaining in human breast tumors using tissue microarrays. These studies suggest that ADAM12L is the primary protease responsible for the activation of EGFR in early stage, lymph node-negative TNBCs. Thus, our results may provide novel insight into the biology of TNBC.
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DOI：
10.1186/bcr1636
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fulford LG;Reis-Filho JS;Ryder K;Jones C;Gillett CE;Hanby A;Easton D;Lakhani SR
通讯作者：
Lakhani SR
影响因子：
3.8
作者：
Duffy MJ;Mullooly M;O'Donovan N;Sukor S;Crown J;Pierce A;McGowan PM
通讯作者：
McGowan PM
DOI：
10.1158/1541-7786.mcr-11-0100
发表时间：
2011-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Fröhlich C;Nehammer C;Albrechtsen R;Kronqvist P;Kveiborg M;Sehara-Fujisawa A;Mercurio AM;Wewer UM
通讯作者：
Wewer UM
TIEG1 通过抑制表皮生长因子受体 (EGFR) 转录和 EGFR 信号通路来抑制乳腺癌侵袭和转移
影响因子：
5.3
作者：
Jin, Wei;Chen, Bo-bin;Shao, Zhi-ming
通讯作者：
Shao, Zhi-ming
影响因子：
50.5
作者：
Corkery, B.;Crown, J.;O'Donovan, N.
通讯作者：
O'Donovan, N.