Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance
Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance
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DOI：
10.1093/carcin/bgu237
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发表时间：
2015-01-01
期刊：
影响因子：
4.7
通讯作者：
Furth, Priscilla A.
中科院分区：
文献类型：
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作者：
Dabydeen, Sarah A.;Kang, Keunsoo;Furth, Priscilla A.
对他莫昔芬和来曲唑的不同反应显示了基因工程小鼠雌激素-ER通路中两种不同的病变，RNA-seq证明了免疫相关基因表达与他莫昔芬耐药的关联，当他莫昔芬耐药时，来曲唑是一种有效的替代品。芳香化酶和雌激素受体（ER）的表达增加与乳腺癌有关。为了研究对内分泌治疗的反应或抗性，采用了Esr 1或CYP 19 A1靶向过表达至乳腺上皮细胞的小鼠，这代表了雌激素途径信号传导中的两种直接病理生理干预。Esr 1和CYP 19 A1过表达小鼠对来曲唑均有反应，增生性肺泡结节患病率降低，乳腺上皮细胞增殖减少。CYP 19 A1过表达小鼠对他莫昔芬敏感，但Esr 1过表达小鼠对他莫昔芬耐药。ER表达的增加与他莫昔芬耐药有关，但孕酮受体、pSTAT 3、pSTAT 5、细胞周期蛋白D1或细胞周期蛋白E水平与反应或耐药无关。使用这些模型和第二个他莫昔芬耐药模型，BRCA 1缺陷/Trp 53单倍不足小鼠，采用RNA测序（RNA-seq）寻找预测他莫昔芬耐药的转录组。68个与免疫系统处理相关的基因在他莫昔芬耐药的Esr 1和Brca 1缺陷小鼠中上调，而与芳香族化合物代谢过程相关的基因在他莫昔芬敏感的CYP 19 A1小鼠中上调。干扰素调节因子7被鉴定为调节这68个免疫加工基因的关键转录因子。两个基因座编码新的转录与人类免疫球蛋白类多肽1的高度同源性独特上调他莫昔芬耐药模型。来曲唑被证明是他莫昔芬的成功替代品。进一步研究与他莫昔芬耐药性相关的转录变化，包括免疫相关基因，可以扩大我们的机制理解，并导致预测逃逸或对内分泌治疗反应的生物标志物。
Differential responses to tamoxifen and letrozole shown with two different lesions in the estrogen-ER pathway in genetically engineered mice, RNA-seq demonstrated an association of immune-related gene expression with tamoxifen resistance, and letrozole was an effective alternative when tamoxifen resistance was present.Response to breast cancer chemoprevention can depend upon host genetic makeup and initiating events leading up to preneoplasia. Increased expression of aromatase and estrogen receptor (ER) is found in conjunction with breast cancer. To investigate response or resistance to endocrine therapy, mice with targeted overexpression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 overexpressing mice responded to letrozole with reduced hyperplastic alveolar nodule prevalence and decreased mammary epithelial cell proliferation. CYP19A1 overexpressing mice were tamoxifen sensitive but Esr1 overexpressing mice were tamoxifen resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance were found. RNA-sequencing (RNA-seq) was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1- and Brca1-deficient mice, whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon regulatory factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human immunoglobulin lambda-like polypeptide 1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies.