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

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Abbreviations

11βHSD:

11Beta-hydroxysteroid dehydrogenase

11βHSD1:

11Beta-hydroxysteroid dehydrogenase type 1

11βHSD2:

11Beta-hydroxysteroid dehydrogenase type 2

95% CI:

95% Confidence interval

AR:

Androgen receptor

DEX:

Dexamethasone

DFS:

Disease-free survival

DHT:

Dihydrotestosterone

ER:

Estrogen receptor

GC:

Glucocorticoid

GR:

Glucocorticoid receptor

GRE:

Glucocorticoid response element

HER2:

Human epidermal growth factor receptor 2

LI:

Labeling index

OR:

Odds ratio

OS:

Overall survival

PR:

Progesterone receptor

qRT-PCR:

Quantitative real-time polymerase chain reaction

SGK1:

Serum and glucocorticoid-regulated kinase-1

TNBC:

Triple-negative breast cancer

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Acknowledgements

We thank the members of the Department of Pathology and the Department of Breast and Endocrine Surgical Oncology in Tohoku University Graduate School of Medicine for their support.

Funding

This study was not funded by any grant.

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Authors and Affiliations

  1. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Ayako Kanai, Minoru Miyashita & Takanori Ishida

  2. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Ayako Kanai, Keely May McNamara, Erina Iwabuchi, Yoshiaki Onodera, Fouzia Guestini, Freeha Khalid & Hironobu Sasano

  3. Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Yasuhiro Miki

  4. Sagara Hospital, 3-31, Matsubara-cho, Kagoshima, Kagoshima, 892-0833, Japan

    Yasuaki Sagara, Yasuyo Ohi & Yoshiaki Rai

  5. Department of Pathology and Laboratory Medicine, Kurume University Medical Center, 155-1, Kokubu-machi, Kurume, Fukuoka, 839-0863, Japan

    Rin Yamaguchi

  6. JCHO Kurume General Hospital, 21, Kushihara-machi, Kurume, Fukuoka, 830-0013, Japan

    Maki Tanaka

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  1. Ayako Kanai
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Corresponding author

Correspondence to Keely May McNamara.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees (Tohoku University Hospital: 2018-1-191, Sagara Hospital: 15-2, JCHO Kurume General Hospital: 148) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kanai, A., McNamara, K.M., Iwabuchi, E. et al. Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling. Breast Cancer Res Treat 180, 97–110 (2020). https://doi.org/10.1007/s10549-020-05523-7

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