Department of Medicine, Cedars-Sinai Medical Center, Academic Affairs, Room 2015, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
Endocrinology. 2012 Aug;153(8):3679-91. doi: 10.1210/en.2012-1056. Epub 2012 May 25.
Although prolactinomas can be effectively treated with dopamine agonists, about 20% of patients develop dopamine resistance or tumor recurrence after surgery, indicating a need for better understanding of underlying disease mechanisms. Although estrogen-induced rat prolactinomas have been widely used to investigate the development of this tumor, the extent that the model recapitulates features of human prolactinomas is unclear. To prioritize candidate genes and gene sets regulating human and rat prolactinomas, microarray results derived from human prolactinomas and pituitaries of estrogen-treated ACI rats were integrated and analyzed. A total of 4545 differentially expressed pituitary genes were identified in estrogen-treated ACI rats [false discovery rate (FDR) < 0.01]. By comparing pituitary microarray results derived from estrogen-treated Brown Norway rats (a strain not sensitive to estrogen), 4073 genes were shown specific to estrogen-treated ACI rats. Human prolactinomas exhibited 1177 differentially expressed genes (FDR < 0.05). Combining microarray data derived from human prolactinoma and pituitaries of estrogen-treated ACI rat, 145 concordantly expressed genes, including E2F1, Myc, Igf1, and CEBPD, were identified. Gene set enrichment analysis revealed that 278 curated pathways and 59 gene sets of transcription factors were enriched (FDR < 25%) in estrogen-treated ACI rats, suggesting a critical role for Myc, E2F1, CEBPD, and Sp1 in this rat prolactinoma. Similarly increased Myc, E2F1, and Sp1 expression was validated using real-time PCR and Western blot in estrogen-treated Fischer rat pituitary glands. In summary, characterization of individual genes and gene sets in human and in estrogen-induced rat prolactinomas validates the model and provides insights into genomic changes associated with this commonly encountered pituitary tumor.
虽然多巴胺激动剂可以有效地治疗泌乳素瘤，但约 20%的患者在手术后会出现多巴胺耐药或肿瘤复发，这表明需要更好地了解潜在的疾病机制。虽然雌激素诱导的大鼠泌乳素瘤已被广泛用于研究这种肿瘤的发生，但该模型再现人类泌乳素瘤特征的程度尚不清楚。为了确定调节人类和大鼠泌乳素瘤的候选基因和基因集，整合和分析了源自人类泌乳素瘤和雌激素处理的 ACI 大鼠垂体的微阵列结果。在雌激素处理的 ACI 大鼠中鉴定出 4545 个差异表达的垂体基因[错误发现率 (FDR) <0.01]。通过比较源自雌激素处理的布朗诺威大鼠（对雌激素不敏感的品系）的垂体微阵列结果，显示出 4073 个基因特异性存在于雌激素处理的 ACI 大鼠中。人类泌乳素瘤表现出 1177 个差异表达的基因(FDR <0.05)。将源自人类泌乳素瘤和雌激素处理的 ACI 大鼠垂体的微阵列数据结合起来，鉴定出 145 个一致表达的基因，包括 E2F1、Myc、Igf1 和 CEBPD。基因集富集分析显示，在雌激素处理的 ACI 大鼠中富集了 278 个已验证的途径和 59 个转录因子基因集（FDR <25%），表明 Myc、E2F1、CEBPD 和 Sp1 在这种大鼠泌乳素瘤中起着关键作用。使用实时 PCR 和 Western blot 在雌激素处理的 Fischer 大鼠垂体中验证了 Myc、E2F1 和 Sp1 表达的相似增加。总之，对人类和雌激素诱导的大鼠泌乳素瘤中的单个基因和基因集的特征描述验证了该模型，并提供了与这种常见垂体瘤相关的基因组变化的见解。
