Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells

被引:69
作者
Nabha, SM
Glaros, S
Hong, M
Lykkesfeldt, AE
Schiff, R
Osborne, K
Reddy, KB
机构
[1] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA
[2] Danish Canc Soc, Inst Canc Biol, Dept Tumor Endocrinol, DK-2100 Copenhagen, Denmark
[3] Baylor Coll Med, Ctr Brest, Houston, TX 77030 USA
[4] Methodist Hosp, Houston, TX 77030 USA
关键词
tamoxifen resistance; PKC-delta; MAPK; AKT; breast cancer;
D O I
10.1038/sj.onc.1208502
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3166 / 3176
页数:11
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