Nabha Sanaa M, Glaros Selina, Hong Meng, Lykkesfeldt Anne E, Schiff Rachel, Osborne Kent, Reddy Kaladhar B
Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Oncogene. 2005 Apr 28;24(19):3166-76. doi: 10.1038/sj.onc.1208502.
Acquired resistance to tamoxifen (Tam) in breast cancer patients is a serious therapeutic problem. We have previously reported that protein kinase C-delta (PKC-delta) plays a major role in estrogen (E2)-mediated cell proliferation. To determine if PKC-delta is one of the major alternate signaling pathways that supports cell growth in the presence of Tam, we determined the levels of PKC isoforms in four different models of antiestrogen-resistant cells. Three out of four antiestrogen resistance cell lines (Tam/MCF-7, ICI/MCF-7 and HER-2/MCF-7) expressed significantly high levels of both total and activated PKC-delta levels compared to sensitive cells. Estrogen receptor (ER) alpha content and function are maintained in all the antiestrogen-resistant cell lines. Overexpressing active PKC-delta in Tam-sensitive MCF-7 cells (PKC-delta/MCF-7) led to Tam resistance both in vitro and in vivo. Inhibition of PKC-delta by rottlerin (a relatively specific inhibitor of PKC-delta) or siRNA significantly inhibited estrogen- and Tam-induced growth in antiestrogen-resistant cells. PKC-delta levels are significantly higher in Tam-resistant tumors compared to Tam-sensitive tumors in xenograft model (P<0.05). Taken together, these data suggest that PKC-delta plays a major role in antiestrogen resistance in breast tumor cells and thus provides a new target for treatment.
乳腺癌患者对他莫昔芬（Tam）产生获得性耐药是一个严重的治疗难题。我们之前报道过蛋白激酶C-δ（PKC-δ）在雌激素（E2）介导的细胞增殖中起主要作用。为了确定PKC-δ是否是在存在Tam的情况下支持细胞生长的主要替代信号通路之一，我们在四种不同的抗雌激素耐药细胞模型中测定了PKC同工型的水平。与敏感细胞相比，四种抗雌激素耐药细胞系中的三种（Tam/MCF-7、ICI/MCF-7和HER-2/MCF-7）总PKC-δ水平和活化PKC-δ水平均显著升高。所有抗雌激素耐药细胞系中雌激素受体（ER）α的含量和功能均得以维持。在对Tam敏感的MCF-7细胞（PKC-δ/MCF-7）中过表达活性PKC-δ导致体外和体内对Tam耐药。rottlerin（一种相对特异性的PKC-δ抑制剂）或小干扰RNA（siRNA）抑制PKC-δ可显著抑制抗雌激素耐药细胞中雌激素和Tam诱导的生长。在异种移植模型中，与对Tam敏感的肿瘤相比，对Tam耐药的肿瘤中PKC-δ水平显著更高（P<0.05）。综上所述，这些数据表明PKC-δ在乳腺肿瘤细胞的抗雌激素耐药中起主要作用，因此提供了一个新的治疗靶点。
