A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.
A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance.
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DOI：
10.1158/1078-0432.ccr-10-2567
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Miller TW;Balko JM;Ghazoui Z;Dunbier A;Anderson H;Dowsett M;González-Angulo AM;Mills GB;Miller WR;Wu H;Shyr Y;Arteaga CL
尽管大多数雌激素受体α（ER）阳性乳腺癌患者最初对内分泌治疗有反应，但许多患者最终对抗雌激素产生耐药性。然而，抗雌激素抵抗的机制和生物标志物预测这种阻力是欠发达。我们调整了四种ER+人乳腺癌细胞系，使其在雌激素耗尽的培养基中生长。通过比较长期雌激素剥夺（LTED）细胞与其亲本细胞的表达谱，开发了雌激素非依赖性的基因签名。我们评估了LTED信号预测肿瘤对芳香化酶抑制剂新辅助治疗的反应和辅助他莫昔芬治疗后的疾病结局的能力。我们利用LTED细胞基因表达谱的基因集分析（GSA）和功能丧失的方法来鉴定与内分泌治疗抗性有因果关系的途径。LTED基因表达特征可预测不同患者队列中阿那曲唑和来曲唑新辅助治疗后的高肿瘤细胞增殖。在两项关于他莫昔芬辅助治疗患者的研究中，该特征也预测了较差的无复发生存率。LTED细胞中表达谱的生物信息学询问揭示了MYC激活的特征。MYC激活信号和高MYC蛋白水平均预示着他莫昔芬治疗后的不良结局。最后，敲低MYC抑制LTED细胞生长。一种来自ER+乳腺癌细胞的基因表达特征，具有获得性激素依赖性，可预测肿瘤对芳香化酶抑制剂的反应，并与他莫昔芬耐药的临床标志物相关。在某些情况下，MYC途径的激活与这种抗性相关。
Although most patients with estrogen receptor α (ER)-positive breast cancer initially respond to endocrine therapy, many ultimately develop resistance to antiestrogens. However, mechanisms of antiestrogen resistance and biomarkers predictive of such resistance are underdeveloped. We adapted four ER+ human breast cancer cell lines to grow in an estrogen-depleted medium. A gene signature of estrogen independence was developed by comparing expression profiles of long-term estrogen-deprived (LTED) cells to their parental counterparts. We evaluated the ability of the LTED signature to predict tumor response to neoadjuvant therapy with an aromatase inhibitor, and disease outcome following adjuvant tamoxifen. We utilized Gene Set Analysis (GSA) of LTED cell gene expression profiles and a loss-of-function approach to identify pathways causally associated with resistance to endocrine therapy. The LTED gene expression signature was predictive of high tumor cell proliferation following neoadjuvant therapy with anastrozole and letrozole, each in different patient cohorts. This signature was also predictive of poor recurrence-free survival in two studies of patients treated with adjuvant tamoxifen. Bioinformatic interrogation of expression profiles in LTED cells revealed a signature of MYC activation. The MYC activation signature and high MYC protein levels were both predictive of poor outcome following tamoxifen therapy. Finally, knockdown of MYC inhibited LTED cell growth. A gene expression signature derived from ER+ breast cancer cells with acquired hormone independence predicted tumor response to aromatase inhibitors and associated with clinical markers of resistance to tamoxifen. In some cases, activation of the MYC pathway was associated with this resistance.