Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease

• Published in: Human pathology 2018-07, Vol.77, p.152-158
• Main Authors: Mai, Ruiqin, Zhou, Songxia, Zhou, Shuqin, Zhong, Weixiang, Hong, Liangli, Wang, Yuanyuan, Lu, Shanming, Pan, Jikai, Huang, Yuansheng, Su, Mingwan, Crawford, Richard, Zhou, Youwen, Zhang, Guohong
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Androgens; Antigens; Biomarkers, Tumor - analysis; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Disease; EMPD; Female; FOXA1; Gene expression; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - metabolism; Humans; Male; Middle Aged; MPD; Paget Disease, Extramammary - diagnosis; Paget Disease, Extramammary - genetics; Paget Disease, Extramammary - pathology; Paget's disease; Paget's Disease, Mammary - diagnosis; Paget's Disease, Mammary - genetics; Paget's Disease, Mammary - pathology; Receptors, Estrogen - metabolism
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2017.12.030

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 FOXA1, suggesting similarity in cell-specific transcriptional regulation. Further, FOXA1 may be a useful molecular target for developing PD therapies. •FOXA1 was 1 of 5 top upregulated genes by transcriptome analyses in extramammary Paget's disease.•FOXA1 expression was frequent in both MPD and EMPD by validation cohort.•MPD and EMPD share similarities at the level of cell-specific transcriptional regulation.