Department of Medicine, Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
Breast Cancer Res Treat. 2012 Sep;135(2):415-32. doi: 10.1007/s10549-012-2164-8. Epub 2012 Jul 24.
Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors ±estrogen and ±endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naïve tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies.
在开发内分泌抵抗过程中绕过雌激素受体 (ER) 信号仍然是乳腺癌患者疾病进展和死亡的最常见原因。迄今为止，针对 ER 在乳腺癌中的作用的大多数分子研究都是在源自晚期疾病的细胞系模型中进行的。在这里，我们描述了用于研究肿瘤内激素和受体作用的患者来源的 ER+ 管腔乳腺癌模型。从手术后的患者获得的人乳腺肿瘤样本在雌激素补充下立即移植到 NOD/SCID 或 NOD/SCID/ILIIrg(-/-) 小鼠中。建立了五个可移植的患者来源的 ER+ 乳腺癌异种移植物，源自原发性和转移性病例。评估了它们对雌激素的依赖性、甾体受体表达、癌症干细胞含量和内分泌治疗反应。在选择的肿瘤中确定了基因表达模式 ± 雌激素和 ± 内分泌治疗。异种移植物在形态上类似于起源的患者肿瘤，并在多个传代中表达相似水平的 ER（5-99%）和孕激素和雄激素受体。四个肿瘤异种移植物对雌激素依赖，他莫昔芬或雌激素撤药（EWD）治疗消除了雌激素依赖性生长和/或肿瘤形态。对选择的肿瘤中的 ER 转录组进行分析表明，除了确定一小部分共同的雌激素调节基因外，ER 作用机制和下游激活的信号网络存在明显差异。用他莫昔芬或 EWD 对一个未治疗的肿瘤进行治疗显示出相似的表型反应，但雌激素依赖性转录和受影响的信号通路相对较少相似。几个核心的雌激素中心基因与传统的细胞系模型共享。然而，一些新的肿瘤特异性雌激素调节的潜在靶基因，如癌症/睾丸抗原 45，被发现。这些结果表明在乳腺癌中映射保守和肿瘤特有的 ER 程序的重要性。此外，它们强调了原发性异种移植物对于更好地理解 ER+乳腺癌异质性和开发个性化治疗的重要性。
