Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease
Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease
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DOI：
10.1016/j.humpath.2017.12.030
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发表时间：
2018-07-01
期刊：
影响因子：
3.3
通讯作者：
Zhang, Guohong
中科院分区：
文献类型：
--
作者：
Mai, Ruiqin;Zhou, Songxia;Zhang, Guohong
Paget病（PD）是一种罕见的上皮内腺癌，其发病机制尚不清楚。有两种解剖亚型：乳腺（MPD）和乳腺外（EMPD）。人们对它们的分子特性知之甚少。我们的目标是发现PD及其亚型的新分子标记。在发现阶段，我们使用转录组分析来揭示与正常皮肤相比，EMPD活检组织中表达差异最大的基因和途径。在验证阶段，我们对MPD （n = 86）、EMPD （n = 59）和正常皮肤（n = 21）的独立活检进行了最有希望的标记物（FOXA1）和其他从文献综述中选择的标记物（GATA3、雌激素受体[ER]和雄激素受体[AR]）的免疫组织化学分析。转录组分析显示，210个基因在EMPD和正常皮肤之间差异表达超过10倍。这些基因参与乳腺和汗腺发育（FOXA1）和免疫调节，以及表皮分化。免疫组化染色显示FOXA1在88%的MPD和EMPD中呈阳性，GATA3在67%的MPD和77%的EMPD中呈阳性，ER在9%的MPD和19%的EMPD中呈阳性。最后，AR在33%的PD和54%的EMPD中呈阳性。乳腺Paget病和EMPD共享腺体发育调节基因foxa1的失调，提示细胞特异性转录调控的相似性。此外，FOXA1可能是开发PD治疗的有用分子靶点。(C) 2018爱思唯尔公司版权所有。
Paget's disease (PD) is an uncommon intraepithelial adenocarcinoma with unknown pathogenesis. There are two anatomic subtypes: mammary (MPD) and extramammary (EMPD). Little is known about their molecular characteristics. Our objective was to discover novel molecular markers for PD and its subtypes. In the discovery phase, we used transcriptome analyses to uncover the most differentially expressed genes and pathways in EMPD biopsies compared with normal skin. In the validation phase, we performed immunohistochemistry analyses on the most promising marker (FOXA1) and other markers selected from a literature review (GATA3, estrogen receptor [ER], and androgen receptor [AR]) on independent biopsies of MPD (n = 86), EMPD (n = 59), and normal skin (n = 21). Transcriptome analyses revealed 210 genes differentially expressed more than 10-fold between EMPD and normal skin. These genes are involved in mammary and sweat gland development (FOXA1) and immune regulation, as well as epidermal differentiation. Immunohistochemistry staining revealed that FOXA1 was positive in 88% of both MPD and EMPD, whereas GATA3 was positive in 67% of MPD and 77% of EMPD, and ER was positive in 9% of MPD and 19% of EMPD. Finally, AR was positive in 33% of PD and 54% of EMPD. Mammary Paget's disease and EMPD share dysregulation of the glandular developmental regulator gene FOXA 1, suggesting similarity in cell-specific transcriptional regulation. Further, FOXA1 may be a useful molecular target for developing PD therapies. (C) 2018 Elsevier Inc. All rights reserved.