Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings.
Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings.
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DOI：
10.1186/s13058-018-1064-1
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发表时间：
2018-11-20
期刊：
影响因子：
--
通讯作者：
Hopkins AM
中科院分区：
文献类型：
--
作者：
Leech AO;Vellanki SH;Rutherford EJ;Keogh A;Jahns H;Hudson L;O'Donovan N;Sabri S;Abdulkarim B;Sheehan KM;Kay EW;Young LS;Hill ADK;Smith YE;Hopkins AM
连接粘附分子-A（JAM-A）是一种粘附分子，其在乳腺肿瘤组织上的过表达与侵袭性癌症表型相关，包括人表皮生长因子受体-2（HER 2）阳性疾病。由于JAM-A已被描述为调节乳腺癌细胞中的HER 2表达，我们假设JAM依赖性HER 2稳定可能参与对HER 2靶向治疗的耐药性。使用抗HER 2药物耐药的乳腺癌细胞系模型，我们研究了JAM-A表达和JAM-A沉默对生化/功能参数的影响。我们还测试了改变的JAM-A表达/加工是否支持药物敏感细胞和耐药细胞之间的差异，并作为对HER 2靶向治疗产生耐药性的患者的生物标志物。沉默JAM-A增强了抗HER 2治疗在曲妥珠单抗和拉帕替尼耐药乳腺癌细胞中的抗增殖作用，并进一步降低了药物处理细胞中的HER 2蛋白表达和Akt磷酸化。在耐药模型中观察到的表皮生长因子受体表达增加在JAM-A沉默后标准化。JAM-A在抗HER 2治疗后疾病复发的HER 2阳性患者的所有小队列中高度表达。在另一个曲妥珠单抗治疗耐药的患者队列中，高JAM-A表达也与诊断时的转移性疾病相关。重要的是，在耐药细胞系中JAM-A的切割增加，同时ADAM-10和-17金属蛋白酶的表达增加。药理学抑制或遗传沉默研究表明，ADAM-10在减少JAM-A切割和部分重新使耐药细胞对HER 2靶向药物的抗增殖作用敏感方面具有特殊作用。在功能上，重组切割的JAM-A增强了乳腺癌细胞的体外侵袭和半体内模型中的侵袭和增殖。最后，在一小群HER 2阳性患者的血清中可检测到裂解的JAM-A，并且与对HER 2靶向治疗的抗性显著相关。总的来说，我们的数据表明了一种新的模型，其中JAM-A的表达和切割增加驱动致瘤行为，并作为对HER 2靶向治疗耐药的生物标志物和潜在治疗靶点。本文的在线版本（10.1186/s13058-018-1064-1）包含补充材料，可供授权用户使用。
Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies. The online version of this article (10.1186/s13058-018-1064-1) contains supplementary material, which is available to authorized users.
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影响因子：
--
作者：
de Melo Gagliato D;Jardim DL;Marchesi MS;Hortobagyi GN
通讯作者：
Hortobagyi GN
影响因子：
8.8
作者：
Kuefer, R;Hofer, M D;Altug, V;Zorn, C;Genze, F;Kunzi-Rapp, K;Hautmann, R E;Gschwend, J E
通讯作者：
Gschwend, J E
影响因子：
3.8
作者：
Kang SH;Kang KW;Kim KH;Kwon B;Kim SK;Lee HY;Kong SY;Lee ES;Jang SG;Yoo BC
通讯作者：
Yoo BC
影响因子：
6.7
作者：
Babinska, A;Kedees, MH;Kornecki, E
通讯作者：
Kornecki, E
影响因子：
3.1
作者：
Araki, Kazuhiro;Fukada, Ippei;Ito, Yoshinori
通讯作者：
Ito, Yoshinori