Abstract
Hidradenitis Suppurativa (HS) is an autoinflammatory skin disease more common in women and associated with hyper-androgenic disorders such as polycystic ovary syndrome. HS is characterized by chronic recurrent deep-seated painful nodules and draining tunnels in skin areas that follow the distribution of pubertal terminal hair growth. In women, HS disease activity varies with hormonal fluctuation across the menstrual cycle and pregnancy. Anti-androgens have shown promise in treatment of HS, but the pathophysiologic link between sex hormones and HS is unclear. We sought to further elucidate the role of sex hormones in the pathogenesis of HS. Objective: To determine if there is differential estrogen and androgen regulated gene expression in lesional compared to non-lesional skin transcriptome in HS patients. Methods: (a) We analyzed mRNA microarray data from lesional and non-lesional HS skin (GEO, GSE72702) (Blok JL, Br J Dermatol. 2016;174(6):1392). Inflammatory lesional skin from affected axilla or groin and non-lesional skin from the upper arm or leg was obtained from 17 patients with moderate to severe HS. We then examined differential expression of hormone regulated genes identified in existing androgen and estrogen gene expression signatures from prostate cancer cells [(VCaP treated with dihydrotestosterone (DHT)] and breast cancer cells [MCF7 treated with 17 beta-estradiol, (E2)] in the lesional and non-lesional skin transcriptomes of the HS patients. We identified overlap between the sets of genes that were either both upregulated or both repressed in HS lesions and the hormone-responsive prostate and breast cancer cell line models. Significance of differential gene expression was defined as FDR-adjusted p-value for two-tailed Student t-test less than 0.05. (b) After overlapping genes were identified, we used GeneGo Metacore pathway analysis software to explore the functional significance of the identified genes. Results: (a) Of the 3379 E2-upregulated probe sets in MCF7 breast cancer cells, 647 were significantly upregulated and 584 of 2871 E2-downregulated probe sets were significantly downregulated in HS lesions. Of the 1328 DHT-upregulated probe sets in prostate cancer cells, 341 were significantly upregulated and 196 of the 1251 DHT-downregulated probe sets were significantly downregulated in HS lesions. (b) Initial pathway analysis indicates that DHT upregulated genes in HS lesions are strongly enriched in innate immunity pathways, specifically, type 1 interferon signaling and class I MHC antigen presentation. Conclusion: There is substantial overlap between the transcriptional programme of sex steroids and transcriptional changes observed in HS lesional skin. In particular, androgen target genes are significantly enriched in innate immunity pathways, suggesting a functional link between the androgen signaling and the inflammatory process in HS lesions.