Department of Pathology and Laboratory Medicine, St Vincent's University Hospital, Dublin; UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin.
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin; Department of Medical Oncology, St Vincent's University Hospital, Dublin.
Ann Oncol. 2013 Feb;24(2):362-369. doi: 10.1093/annonc/mds279. Epub 2012 Sep 11.
Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors.
Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs.
In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents.
It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.
目前，对于雌激素受体、孕激素受体和 HER2 均为阴性的浸润性乳腺癌患者（即三阴性 (TN) 疾病患者），尚无经过验证的靶向治疗方法。ADAM-17 是一种参与几种配体激活的蛋白酶，这些配体与 EGFR/HER 受体家族结合并促进细胞内信号转导。
在 86 例三阴性和 96 例非三阴性乳腺癌中测量了 ADAM-17 的表达。在一组乳腺癌细胞系中测试了 ADAM-17 特异性抑制剂 PF-5480090（TMI-002，辉瑞）对功能输出的影响。
在这项研究中，我们通过 Western blot 和免疫组化显示，ADAM-17 在 TN 乳腺癌中的表达水平明显高于非 TN 乳腺癌。使用一组培养的乳腺癌细胞系，发现 PF-5480090 可降低 EGFR 配体 TGF-α的释放，降低磷酸化 EGFR 的水平，并以细胞类型依赖性方式阻断细胞增殖。重要的发现是 ADAM-17 活性与 PF-5480090 抑制增殖的程度之间存在显著且中度强相关性（r = 0.809；p = 0.003；n = 11）。在用 PF-5480090 预处理细胞系后，增强了对几种不同细胞毒性药物和抗 EGFR/HER 药物的反应。
抑制 ADAM-17，特别是与化疗或抗 EGFR/HER 抑制剂联合使用，可能是治疗乳腺癌的新方法，包括 TN 疾病患者。
