Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling

Ayako Kanai, Keely May McNamara, Erina Iwabuchi, Yasuhiro Miki, Yoshiaki Onodera, Fouzia Guestini, Freeha Khalid, Yasuaki Sagara, Yasuyo Ohi, Yoshiaki Rai, Rin Yamaguchi, Maki Tanaka, Minoru Miyashita, Takanori Ishida, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Purpose: Chemotherapy is the only current effective systemic treatment for triple-negative breast cancer (TNBC) patients. Therefore, the identification of active biological pathways that could become therapeutic targets is crucial. In this study, considering the well-reported biological roles of glucocorticoid and androgen receptors (GR, AR) in TNBC, we attempted to explore the effects of glucocorticoids (GCs) on cell kinetics as well as the potential interaction between GR and AR in TNBC. Methods: We first explored the association between the status of GR, AR, and/or GCs-metabolizing enzymes such as 11β-hydroxysteroid dehydrogenase (11βHSD) 1 and 2 and the clinicopathological variables of the TNBC patients. Thereafter, we also studied the effects of dexamethasone (DEX) with/without dihydrotestosterone (DHT) on TNBC cell lines by assessing the cell proliferation, migration and GC response genes at the transcriptional level. Results: GR positivity in carcinoma cells was significantly associated with adverse clinical outcome of the patients and AR positivity was significantly associated with lower histological grade and Ki-67 labeling index of the cases examined. In particular, AR positivity was significantly associated with decreased risks of developing recurrence in GR-positive TNBC patients. The subsequent in vitro studies revealed that DEX-promoted cell migration was inhibited by the co-treatment with DHT in GR/AR double-positive HCC38 cells. In addition, DHT inhibited the DEX-increased serum and glucocorticoid-regulated kinase-1 (SGK1) mRNA expression. Conclusion: This is the first study to reveal that the interaction of GR and AR did influence the clinical outcome of TNBC patients and GCs induced cell migration in TNBC cells.

Original languageEnglish
Pages (from-to)97-110
Number of pages14
JournalBreast Cancer Research and Treatment
Volume180
Issue number1
DOIs
Publication statusPublished - 2020 Feb 1
Externally publishedYes

Keywords

  • Androgen receptor
  • Cell migration
  • Glucocorticoid receptor
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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