Department of Surgery, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Pathobiology Section, School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
Breast Cancer Res. 2018 Nov 20;20(1):140. doi: 10.1186/s13058-018-1064-1.
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.
连接黏附分子-A（JAM-A）是一种黏附分子，其在乳腺肿瘤组织中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（HER2）阳性疾病。由于 JAM-A 已被描述为调节乳腺癌细胞中的 HER2 表达，我们假设 JAM 依赖性的 HER2 稳定作用可能参与了对 HER2 靶向治疗的耐药性。
使用对抗 HER2 药物耐药的乳腺癌细胞系模型，我们研究了 JAM-A 的表达，以及 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/加工是否是药物敏感和耐药细胞之间差异的基础，并作为对 HER2 靶向治疗产生耐药性的患者的生物标志物。
沉默 JAM-A 增强了曲妥珠单抗和拉帕替尼耐药乳腺癌细胞中抗 HER2 治疗的增殖抑制作用，并进一步降低了药物处理细胞中 HER2 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 沉默后得到了正常化。JAM-A 在一小部分 HER2 阳性患者中高度表达，这些患者在抗 HER2 治疗后疾病复发。在另一组对曲妥珠单抗耐药的患者队列中，JAM-A 的高表达也与诊断时的转移性疾病相关。重要的是，药物耐药细胞系中 JAM-A 的切割增加与 ADAM-10 和 -17 金属蛋白酶表达增加有关。药理学抑制或基因沉默研究表明，ADAM-10 在减少 JAM-A 切割和部分重新敏化耐药细胞对 HER2 靶向药物的增殖抑制作用方面具有特殊作用。功能上，重组切割的 JAM-A 增强了乳腺癌细胞在体外的侵袭能力，以及在半体内模型中的侵袭和增殖能力。最后，在一小部分 HER2 阳性患者的血清中可检测到切割的 JAM-A，并与对 HER2 靶向治疗的耐药性显著相关。
总的来说，我们的数据表明了一种新的模型，即 JAM-A 的表达增加和切割驱动肿瘤发生行为，并作为对 HER2 靶向治疗耐药的生物标志物和潜在治疗靶点。
