Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer.
Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer.
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DOI：
10.1186/bcr2858
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Naderi A;Chia KM;Liu J
雌激素受体阴性(ER-)乳腺癌是一种治疗选择有限的异质性疾病。分子顶分泌型占ER肿瘤的50%，其特征是包括雄激素受体(AR)在内的类固醇反应基因的过度表达。我们最近在分子顶分泌亚型中发现了AR和细胞外信号调节激酶(ERK)信号通路之间的正反馈回路。在这个反馈环中，AR通过ErbB2的介导调节ERK的磷酸化，而ERK-CREB1信号又调节分子顶分泌细胞中AR的转录。在这项研究中，我们研究了AR-ERK反馈环在分子顶分泌型乳腺癌中的治疗意义。我们用四甲基偶氮唑盐比色法和Annexin V细胞凋亡率法检测了AR抑制剂氟他胺和MEK抑制剂CI-1040对分子顶分泌细胞系MDA-MB-453、肝癌-1954和肝癌-202的协同作用。用组合指数(CI)法测定协同作用。此外，我们在分子顶分泌亚型的异种移植模型中检测了氟他胺和MEK抑制剂PD0325901之间的体内协同作用。评估体内治疗对肿瘤生长、细胞增殖和血管生成的影响。我们通过细胞存活率和细胞凋亡率分析，证明了氟他胺和CI-1040在四种剂量组合下对三种分子顶分泌细胞系联合治疗的协同CI值。此外，我们在体内显示，氟他胺和MEK抑制剂PD0325901联合治疗在抑制肿瘤生长、细胞增殖和血管生成方面的疗效显著高于这些药物单独治疗。此外，我们的数据表明，氟他胺和CI-1040在分子顶分泌型曲妥珠单抗耐药模型中具有协同作用。值得注意的是，联合治疗对曲妥珠单抗耐药细胞的疗效与消除在曲妥珠单抗耐药过程中产生的ERK磷酸化水平的增加有关。在这项研究中，我们展示了AR和MEK抑制剂在分子顶分泌型乳腺癌中的体外和体内协同作用。此外，我们还表明，与这些抑制剂联合治疗可以克服分子顶分泌细胞对曲妥珠单抗的耐药性。因此，AR和MEK抑制剂的联合治疗策略可能为ER-/AR+亚型乳腺癌提供一个有吸引力的治疗选择。
Estrogen receptor-negative (ER-) breast cancer is a heterogeneous disease with limited therapeutic options. The molecular apocrine subtype constitutes 50% of ER-tumors and is characterized by overexpression of steroid response genes including androgen receptor (AR). We have recently identified a positive feedback loop between the AR and extracellular signal-regulated kinase (ERK) signaling pathways in the molecular apocrine subtype. In this feedback loop, AR regulates ERK phosphorylation through the mediation of ErbB2 and, in turn, ERK-CREB1 signaling regulates the transcription of AR in molecular apocrine cells. In this study, we investigated the therapeutic implications of the AR-ERK feedback loop in molecular apocrine breast cancer. We examined a synergy between the AR inhibitor flutamide and the MEK inhibitor CI-1040 in the molecular apocrine cell lines MDA-MB-453, HCC-1954 and HCC-202 using MTT cell viability and annexin V apoptosis assays. Synergy was measured using the combination index (CI) method. Furthermore, we examined in vivo synergy between flutamide and the MEK inhibitor PD0325901 in a xenograft model of the molecular apocrine subtype. The effects of in vivo therapies on tumor growth, cell proliferation and angiogenesis were assessed. We demonstrate synergistic CI values for combination therapy with flutamide and CI-1040 across three molecular apocrine cell lines at four dose combinations using both cell viability and apoptosis assays. Furthermore, we show in vivo that combination therapy with flutamide and MEK inhibitor PD0325901 has a significantly higher therapeutic efficacy in reducing tumor growth, cellular proliferation and angiogenesis than monotherapy with these agents. Moreover, our data suggested that flutamide and CI-1040 have synergy in trastuzumab resistance models of the molecular apocrine subtype. Notably, the therapeutic effect of combination therapy in trastuzumab-resistant cells was associated with the abrogation of an increased level of ERK phosphorylation that was developed in the process of trastuzumab resistance. In this study, we demonstrate in vitro and in vivo synergies between AR and MEK inhibitors in molecular apocrine breast cancer. Furthermore, we show that combination therapy with these inhibitors can overcome trastuzumab resistance in molecular apocrine cells. Therefore, a combination therapy strategy with AR and MEK inhibitors may provide an attractive therapeutic option for the ER-/AR+ subtype of breast cancer.
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DOI：
10.1016/j.radonc.2009.09.006
发表时间：
2009-12
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
--
作者：
Sambade MJ;Camp JT;Kimple RJ;Sartor CI;Shields JM
通讯作者：
Shields JM
影响因子：
5.8
作者：
Liu, Dingxie;Liu, Zhi;Xing, Mingzhao
通讯作者：
Xing, Mingzhao
影响因子：
11.5
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
通讯作者：
Lackner, Mark R.
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
8
作者：
Farmer, P;Bonnefoi, H;Iggo, R
通讯作者：
Iggo, R