A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer

被引:147
作者
Naderi, Ali [1 ]
Hughes-Davies, Luke [1 ]
机构
[1] Univ Queensland, Princess Alexandra Hosp, Canc Biol Program, Diamantina Inst Canc Immunol & Metab Med, Brisbane, Qld 4102, Australia
来源
NEOPLASIA | 2008年 / 10卷 / 06期
关键词
D O I
10.1593/neo.08274
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR). One subtype ( molecular apocrine) has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.
引用
收藏
页码:542 / 548
页数:7
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