Role of androgen signaling in androgen receptor-positive extramammary Paget's disease: Establishment of organoids and their biological analysis as a novel therapeutic target

Yoshio Nakamura, Hayase Mizukami, Keiji Tanese, Takayuki Fusumae, Ikuko Hirai, Masayuki Amagai, Reika Takamatsu, Kohei Nakamura, Hiroshi Nishihara, Tetsuya Takimoto, Masaru Ueno, Hideyuki Saya, Takeru Funakoshi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma that mainly affects the anogenital and axillary regions. Although its etiology has not been fully elucidated, there is evidence that androgen receptors (AR) are expressed in most cases of EMPD. However, the role of androgen signaling in the pathogenesis of EMPD remains unclear. Objective: To evaluate the role of androgen signaling in tumor growth of AR-positive EMPD. Methods: Patient-derived organoids were established and cultured from two AR-positive EMPD patients: one man and one woman. Cultured organoids were treated with androgen agonists and/or antagonists, then subjected to analysis of changes in organoid proliferation, as well as changes in androgen signaling pathway-specific genes. Results: Organoid cultures were established from each EMPD sample. These organoids were immunohistologically and genetically identical to the original tumor. For each organoid sample, viable cell number increased in response to androgen exposure. The mRNA level of Fkbp5, a known AR target gene, increased in a concentration-dependent manner in organoids exposed to the synthetic androgen R1881. Conversely, the AR inhibitor darolutamide suppressed the viable cell number in a concentration-dependent manner. The mRNA expression levels of MKI67 and Fkbp5 were also suppressed by darolutamide. Conclusion: Our results indicate that androgen signaling is a key pathway involved in the growth of AR-positive EMPD. Therefore, androgen signaling inhibition may be a novel treatment option for EMPD patients who require systemic therapy.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalJournal of Dermatological Science
Volume112
Issue number1
DOIs
Publication statusPublished - 10-2023

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology

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