Magnifico Alessandra, Albano Luisa, Campaner Stefano, Campiglio Manuela, Pilotti Silvana, Ménard Sylvie, Tagliabue Elda
Molecular Targeting Unit, Department of Experimental Oncology, National Cancer Institute, Foundation IRCCS, Milan, Italy.
Cancer Res. 2007 Jun 1;67(11):5308-17. doi: 10.1158/0008-5472.CAN-06-3936.
In some HER2-positive breast tumors, cell surface overexpression of HER2 is not associated with gene amplification but may instead rest in altered gene transcription, half-life, or recycling of the oncoprotein. Here, we show that HER2 overexpression in HER2 2+ carcinomas is associated with neither an increase in gene transcription nor a deregulation in the ubiquitin-dependent pathways, but instead seems to be regulated by protein kinase Calpha (PKCalpha) activity. The stimulation of PKCalpha up-regulated HER2 expression, whereas PKCalpha inhibition by pharmacologic treatments and PKCalpha-specific small interfering RNA led to a dramatic down-regulation of HER2 levels only in breast cancer cells HER2 2+. Consistent with the in vitro data, our biochemical analysis of HER2 2+ human primary breast specimens revealed significantly higher levels of phosphorylated PKCalpha compared with HER2-negative tumors. Inhibition of HER2 activation by the tyrosine kinase inhibitor lapatinib led to decreased levels of PKCalpha phosphorylation, clearly indicating a cross-talk between PKCalpha and HER2 molecules. These data suggest that HER2 overexpression in HER2 2+ carcinomas is due to an accumulation of the recycled oncoprotein to the cell surface induced by activated PKCalpha.
在一些HER2阳性乳腺肿瘤中，HER2在细胞表面的过表达与基因扩增无关，而可能在于基因转录、半衰期或癌蛋白循环利用的改变。在此，我们表明，HER2 2+癌中HER2的过表达既不与基因转录增加相关，也不与泛素依赖性途径的失调相关，而是似乎受蛋白激酶Cα（PKCα）活性调控。PKCα的刺激上调了HER2表达，而通过药物治疗抑制PKCα以及PKCα特异性小干扰RNA仅在HER2 2+乳腺癌细胞中导致HER2水平显著下调。与体外数据一致，我们对HER2 2+人原发性乳腺标本的生化分析显示，与HER2阴性肿瘤相比，磷酸化PKCα水平显著更高。酪氨酸激酶抑制剂拉帕替尼对HER2激活的抑制导致PKCα磷酸化水平降低，清楚地表明PKCα与HER2分子之间存在相互作用。这些数据表明，HER2 2+癌中HER2的过表达是由于活化的PKCα诱导循环利用的癌蛋白在细胞表面积累所致。
