Ménard Sylvie, Pupa Serenella Marja, Campiglio Manuela, Tagliabue Elda
Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy.
Oncogene. 2003 Sep 29;22(42):6570-8. doi: 10.1038/sj.onc.1206779.
Overexpression of the human epidermal growth factor-2 (HER2) oncogene in human breast carcinomas has been associated with a more aggressive course of disease. The reason for this association is still unclear, although it has been suggested to rest in increased proliferation, vessel formation, and/or invasiveness. Alternatively, prognosis may not be directly related to the presence of the oncoprotein on the cell membrane, but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile. HER2 has also been associated with sensitivity to anthracyclins and resistance to endocrine therapy, suggesting that tyrosine kinase receptor and hormone receptor pathways represent two major proliferation pathways exclusively active in breast carcinomas, one sensitive to chemotherapeutic drugs and the other to antiestrogens. HER2 currently represents one of the most appropriate targets for specific therapy. Indeed, trastuzumab, a monoclonal antibody directed against the extracellular domain of HER2, is therapeutically active in HER2-positive breast carcinomas. However, a consistent number of HER2-positive tumors is not responsive to HER2-driven therapy, indicating the need for a better understanding of the mechanism of action of this new biological drug in vivo. While preclinical studies suggest antibody-dependent cell cytotoxicity as the major mechanism, determination of NK activity at the time of treatment remains mandatory, especially in patients treated with immunosuppressive drugs. The efficacy of prophylactic vaccination has been fully demonstrated in preclinical models, whereas ongoing studies of active immunotherapy using a variety of vaccination regimens against HER2 in tumor-bearing mice and patients have met with only moderate success.
人类表皮生长因子-2（HER2）癌基因在人类乳腺癌中的过表达与疾病更具侵袭性的病程相关。尽管有人认为这种关联的原因在于增殖增加、血管形成和/或侵袭性增强，但具体原因仍不清楚。另外，预后可能并非直接与细胞膜上癌蛋白的存在相关，而是与由HER2过表达所确定并具有独特基因表达谱特征的乳腺癌亚型有关。HER2还与对蒽环类药物的敏感性以及对内分泌治疗的耐药性相关，这表明酪氨酸激酶受体和激素受体途径代表了仅在乳腺癌中活跃的两种主要增殖途径，一种对化疗药物敏感，另一种对抗雌激素敏感。HER2目前是特异性治疗最合适的靶点之一。确实，曲妥珠单抗是一种针对HER2细胞外结构域的单克隆抗体，在HER2阳性乳腺癌中具有治疗活性。然而，相当数量的HER2阳性肿瘤对HER2驱动的治疗无反应，这表明需要更好地了解这种新型生物药物在体内的作用机制。虽然临床前研究表明抗体依赖性细胞毒性是主要机制，但在治疗时测定自然杀伤细胞（NK）活性仍然是必要的，尤其是在接受免疫抑制药物治疗的患者中。预防性疫苗接种的疗效在临床前模型中已得到充分证明，而目前在荷瘤小鼠和患者中使用多种针对HER2的疫苗接种方案进行主动免疫治疗的研究仅取得了中等程度的成功。
