Giani C, Casalini P, Pupa S M, De Vecchi R, Ardini E, Colnaghi M I, Giordano A, Ménard S
Division of Experimental Oncology E, Istituto Nazionale Tumori, Milan, Italy.
Oncogene. 1998 Jul 30;17(4):425-32. doi: 10.1038/sj.onc.1201954.
c-erbB-2, a member of the tyrosine kinase oncogene family, is overexpressed in about 30% of human breast tumors where it correlates with poor prognosis. In vitro studies have suggested that increased expression of the receptor plays an important role in malignant progression. To better understand the direct effects of p185HER2 overexpression, a human c-erbB-2 expression vector was transfected into the hormone-dependent MCF-7 human breast carcinoma cell line and cell growth was analysed. Unexpectedly, colony formation assay revealed a reduction in the number and size of colonies as compared with mock-transfected cells. In hormone-deprived medium, c-erbB-2 transfected cells acquired growth capability, consistent with previous reports. By contrast, two c-erbB-2-transfected clones grown in complete medium showed a reduced proliferation rate despite the activation of a fully functional oncoprotein capable of autophosphorylation and induction of the MAPK pathway. The number of c-erbB-2-overexpressing cells in the S phase of the cell cycle was about one-half the number of control and mock-transfected cells. Also, overexpression of c-erbB-2 induced overexpression of p21WAF1, pRB hypophosphorylation and a mature differentiated cell phenotype with production of lipid droplets. Functional inactivation of p185HER2 by means of a specific single chain antibody indicated the c-erbB-2-dependence of the observed alterations. These data show that the exogenous overexpression of the c-erbB-2 gene in hormone-dependent breast cancer cells inhibits proliferation and induces differentiation.
c-erbB-2是酪氨酸激酶癌基因家族的成员之一，在约30%的人类乳腺肿瘤中过度表达，与预后不良相关。体外研究表明，该受体表达增加在恶性进展中起重要作用。为了更好地理解p185HER2过度表达的直接影响，将人c-erbB-2表达载体转染到激素依赖性MCF-7人乳腺癌细胞系中，并分析细胞生长情况。出乎意料的是，集落形成试验显示，与mock转染细胞相比，集落的数量和大小有所减少。在激素缺乏的培养基中，c-erbB-2转染细胞获得了生长能力，这与先前的报道一致。相比之下，在完全培养基中生长的两个c-erbB-2转染克隆尽管激活了能够自磷酸化并诱导MAPK途径的完全功能性癌蛋白，但其增殖率仍降低。处于细胞周期S期的c-erbB-2过度表达细胞的数量约为对照和mock转染细胞数量的一半。此外，c-erbB-2的过度表达诱导了p21WAF1的过度表达、pRB的低磷酸化以及具有脂滴产生的成熟分化细胞表型。通过特异性单链抗体对p185HER2进行功能失活表明，观察到的改变依赖于c-erbB-2。这些数据表明，激素依赖性乳腺癌细胞中c-erbB-2基因的外源性过度表达会抑制增殖并诱导分化。
