The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer
The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer
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DOI：
10.1016/j.ajpath.2012.09.021
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发表时间：
2013-01-01
影响因子：
6
通讯作者：
Clevenger, Charles V.
中科院分区：
文献类型：
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作者：
Fiorillo, Alyson A.;Medler, Terry R.;Clevenger, Charles V.
多肽激素催乳素(PRL)通过其同源受体PRLr刺激乳腺上皮细胞的生长、分化和运动。PRLr在大多数乳腺癌中都有表达；然而，它的确切作用仍然不清楚。我们的实验室之前描述了一种新的PRLr信号转导模式，其中Stat5a介导的转录通过配体诱导的PRLr反式激活结构域(TAD)的磷酸化来调节。在这里，我们使用了一个PRLr反式激活缺陷突变体(PRLrYDmut)来鉴定新的TAD特异性靶基因。基因芯片分析发现120个PRL诱导的基因被野生型上调，但没有PRLrYDmut。与对照相比，PRLr表达显著诱导了约4700个PRL诱导基因的表达，而PRLrYDmut除19个基因外，其余基因均被阻断。独创性途径分析发现，PRLR-TAD对涉及癌症和增殖的网络影响最深。为了支持这一点，PRLrYDmut的表达减少了锚定依赖和锚定非依赖的生长。此外，通路分析发现PRLr-tad与雌激素和孕激素受体(ERα/PR)之间存在联系。虽然两个急诊室的阿尔法。NOR PR被确定为PRL的靶基因，TAD突变显著降低ERα/PR的表达和雌激素的反应性。TMA分析显示，作为肿瘤进展的一个函数，核内的PRLr-tad磷酸化显著增加，而不是胞浆内。我们认为，PRLr-tad的磷酸化参与了乳腺癌的发病过程，部分是通过调节ERα和PR，作为乳腺癌的生物标志物具有潜在的实用价值。(Am J Pathol 2013,182：217-233；http://dx.doi.org/10.1016/j.ajpath.2012.09.021)
The polypeptide hormone prolactin (PRL) stimulates breast epithelial cell growth, differentiation, and motility through its cognate receptor, PRLr. PRLr is expressed in most breast cancers; however, its exact role remains elusive. Our laboratory previously described a novel mode of PRLr signaling in which Stat5a-mediated transcription is regulated through ligand-induced phosphorylation of the PRLr transactivation domain (TAD). Herein, we used a PRLr transactivation-deficient mutant (PRLrYDmut) to identify novel TAD-specific target genes. Microarray analysis identified 120 PRL-induced genes upregulated by wild type but not PRLrYDmut. Compared with control, PRLr expression significantly induced expression of approximately 4700 PRL-induced genes, whereas PRLrYDmut ablated induction of all but 19 of these genes. Ingenuity pathway analysis found that the PRLr TAD most profoundly affected networks involving cancer and proliferation. In support of this, PRLrYDmut expression reduced anchorage-dependent and anchorage-independent growth. In addition, pathway analysis identified a Link between the PRLr TAD and the estrogen and progesterone receptors (ER alpha/PR). Although neither ER alpha. nor PR was identified as a PRL target gene, a TAD mutation significantly impaired ER alpha/PR expression and estrogen responsiveness. TMA analysis revealed a marked increase in nuclear, but not cytoplasmic, PRLr TAD phosphorylation as a function of neoplastic progression. We propose that PRLr TAD phosphorytation contributes to breast cancer pathogenesis, in part through regulation of ER alpha and PR, and has potential utility as a biomarker in this disease. (Am J Pathol 2013, 182: 217-233; http://dx.doi.org/10.1016/j.ajpath.2012.09.021)