Skip to main content

Advertisement

SpringerLink
Log in

Induction of SGK1 via glucocorticoid-influenced clinical outcome of triple-negative breast cancer patients

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

Abstract

Purpose

Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive breast malignancy. Glucocorticoid (GC)–glucocorticoid receptor (GR) pathway plays a pivotal role in the cellular responses to various stresses including chemotherapy. Serum- and glucocorticoid-induced kinase-1 (SGK1) is known as an important downstream effector molecule in the GR signaling pathway, we attempted to explore its clinicopathological and functional significance in TNBC in which GR is expressed.

Methods

We first immunolocalized GR and SGK1 and correlated the results with clinicopathological variables and clinical outcome in 131 TNBC patients. We also evaluated the effects of SGK1 on the cell proliferation and migration in TNBC cell lines with administration of dexamethasone (DEX) to further clarify the significance of SGK1.

Results

The status of SGK1 in carcinoma cells was significantly associated with adverse clinical outcome in TNBC patients examined and was significantly associated with lymph node metastasis, pathological stage, and lymphatic invasion of the patients. In particular, SGK1 immunoreactivity was significantly associated with an increased risk of recurrence in GR-positive TNBC patients. Subsequent in vitro studies also demonstrated that DEX promoted TNBC cell migration and the silencing of gene expression did inhibit the cell proliferation and migration of TNBC cells under DEX treatment.

Conclusions

To the best of our knowledge, this is the first study to explore an association between SGK1 and clinicopathological variables and clinical outcome of TNBC patients. SGK1 status was significantly positively correlated with adverse clinical outcome of TNBC patients and promoted carcinoma cell proliferation and migration of carcinoma cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed in the present study are available from the corresponding author upon reasonable request.

References

  1. Yin L, Duan JJ, Bian XW, Yu SC (2020) Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res 22(1):61. https://doi.org/10.1186/s13058-020-01296-5

    Article  PubMed  PubMed Central  Google Scholar 

  2. Belova L, Delgado B, Kocherginsky M, Melhem A, Olopade OI, Conzen SD (2009) Glucocorticoid receptor expression in breast cancer associates with older patient age. Breast Cancer Res Treat 116(3):441–447. https://doi.org/10.1007/s10549-008-0136-9

    Article  CAS  PubMed  Google Scholar 

  3. Abduljabbar R, Negm OH, Lai CF, Jerjees DA, Al-Kaabi M, Hamed MR et al (2015) Clinical and biological significance of glucocorticoid receptor (GR) expression in breast cancer. Breast Cancer Res Treat 150(2):335–346. https://doi.org/10.1007/s10549-015-3335-1

    Article  CAS  PubMed  Google Scholar 

  4. Baker GM, Murphy T, Block T, Nguyen D, Lynch FJ (2015) Development and validation of an immunohistochemistry assay to assess glucocorticoid receptor expression for clinical trials of mifepristone in breast cancer. Cancer Manag Res 7:361–368. https://doi.org/10.2147/CMAR.S91546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Obradovic M, Hamelin B, Manevski N, Couto JP, Sethi A, Coissieux MM et al (2019) Glucocorticoids promote breast cancer metastasis. Nature 567(7749):540–544. https://doi.org/10.1038/s41586-019-1019-4

    Article  CAS  PubMed  Google Scholar 

  6. Miesfeld R, Okret S, Wikstrom AC, Wrange O, Gustafsson JA, Yamamoto KR (1984) Characterization of a steroid hormone receptor gene and mRNA in wild-type and mutant cells. Nature 312(5996):779–781. https://doi.org/10.1038/312779a0

    Article  CAS  PubMed  Google Scholar 

  7. Frank F, Ortlund EA, Liu X (2021) Structural insights into glucocorticoid receptor function. Biochem Soc Trans 49(5):2333–2343. https://doi.org/10.1042/BST20210419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pan D, Kocherginsky M, Conzen SD (2011) Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res 71(20):6360–6370. https://doi.org/10.1158/0008-5472.CAN-11-0362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sorrentino G, Ruggeri N, Zannini A, Ingallina E, Bertolio R, Marotta C et al (2017) Glucocorticoid receptor signalling activates YAP in breast cancer. Nat Commun 8:14073. https://doi.org/10.1038/ncomms14073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang F, Ma Q, Liu Z, Li W, Tan Y, Jin C et al (2017) Glucocorticoid receptor: MegaTrans switching mediates the repression of an ERalpha-regulated transcriptional program. Mol Cell 66(3):321–331. https://doi.org/10.1016/j.molcel.2017.03.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lippman M, Bolan G, Huff K (1976) The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36(12):4602–4609

    CAS  PubMed  Google Scholar 

  12. Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD (2004) Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res 64(5):1757–1764. https://doi.org/10.1158/0008-5472.CAN-03-2546

    Article  CAS  PubMed  Google Scholar 

  13. Pearce LR, Komander D, Alessi DR (2010) The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11(1):9–22. https://doi.org/10.1038/nrm2822

    Article  CAS  PubMed  Google Scholar 

  14. Zhu R, Yang G, Cao Z, Shen K, Zheng L, Xiao J et al (2020) The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star. Ther Adv Med Oncol 12:431411310. https://doi.org/10.1177/1758835920940946

    Article  CAS  Google Scholar 

  15. Sahoo S, Brickley DR, Kocherginsky M, Conzen SD (2005) Coordinate expression of the PI3-kinase downstream effectors serum and glucocorticoid-induced kinase (SGK-1) and Akt-1 in human breast cancer. Eur J Cancer 41(17):2754–2759. https://doi.org/10.1016/j.ejca.2005.07.018

    Article  CAS  PubMed  Google Scholar 

  16. Yao Y, Jiang Q, Jiang L, Wu J, Zhang Q, Wang J et al (2016) Lnc-SGK1 induced by Helicobacter pylori infection and highsalt diet promote Th2 and Th17 differentiation in human gastric cancer by SGK1/Jun B signaling. Oncotarget 7(15):20549–20560. https://doi.org/10.18632/oncotarget.7823

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tang Z, Shen Q, Xie H, Zhou Z, Shi G, Zhang C et al (2018) Serum and glucocorticoid-regulated kinase 1 (SGK1) is a predictor of poor prognosis in non-small cell lung cancer, and its dynamic pattern following treatment with SGK1 inhibitor and gamma-ray irradiation was elucidated. Oncol Rep 39(3):1505–1515. https://doi.org/10.3892/or.2018.6181

    Article  CAS  PubMed  Google Scholar 

  18. Szmulewitz RZ, Chung E, Al-Ahmadie H, Daniel S, Kocherginsky M, Razmaria A et al (2012) Serum/glucocorticoid-regulated kinase 1 expression in primary human prostate cancers. Prostate 72(2):157–164. https://doi.org/10.1002/pros.21416

    Article  CAS  PubMed  Google Scholar 

  19. Kanai A, McNamara KM, Iwabuchi E, Miki Y, Onodera Y, Guestini F et al (2020) Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling. Breast Cancer Res Treat 180(1):97–110. https://doi.org/10.1007/s10549-020-05523-7

    Article  CAS  PubMed  Google Scholar 

  20. McCarty KJ, Miller LS, Cox EB, Konrath J, McCarty KS (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109(8):716–721

    PubMed  Google Scholar 

  21. Ueki S, Fujishima F, Kumagai T, Ishida H, Okamoto H, Takaya K et al (2020) GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: their correlation with therapeutic outcome of neoadjuvant chemotherapy. BMC Cancer 20(1):161. https://doi.org/10.1186/s12885-020-6652-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang Z, Xu Q, Song C, Mi B, Zhang H, Kang H et al (2020) Serum- and glucocorticoid-inducible kinase 1 is essential for osteoclastogenesis and promotes breast cancer bone metastasis. Mol Cancer Ther 19(2):650–660. https://doi.org/10.1158/1535-7163.MCT-18-0783

    Article  CAS  PubMed  Google Scholar 

  23. Lang F, Stournaras C (2013) Serum and glucocorticoid inducible kinase, metabolic syndrome, inflammation, and tumor growth. Hormones (Athens) 12(2):160–171. https://doi.org/10.14310/horm.2002.1401

    Article  PubMed  Google Scholar 

  24. Wu W, Zou M, Brickley DR, Pew T, Conzen SD (2006) Glucocorticoid receptor activation signals through forkhead transcription factor 3a in breast cancer cells. Mol Endocrinol 20(10):2304–2314. https://doi.org/10.1210/me.2006-0131

    Article  CAS  PubMed  Google Scholar 

  25. Isikbay M, Otto K, Kregel S, Kach J, Cai Y, Vander GD et al (2014) Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer 5(2):72–89. https://doi.org/10.1007/s12672-014-0173-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Godbole M, Togar T, Patel K, Dharavath B, Yadav N, Janjuha S et al (2018) Up-regulation of the kinase gene SGK1 by progesterone activates the AP-1-NDRG1 axis in both PR-positive and -negative breast cancer cells. J Biol Chem 293(50):19263–19276. https://doi.org/10.1074/jbc.RA118.002894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee L, Woolley C, Starkey T, Biswas S, Mirshahi T, Bardella C et al (2019) Serum- and glucocorticoid-induced kinase Sgk1 directly promotes the differentiation of colorectal cancer cells and restrains metastasis. Clin Cancer Res 25(2):629–640. https://doi.org/10.1158/1078-0432.CCR-18-1033

    Article  CAS  PubMed  Google Scholar 

  28. Schmidt EM, Gu S, Anagnostopoulou V, Alevizopoulos K, Foller M, Lang F, Stournaras C (2012) Serum- and glucocorticoid-dependent kinase-1-induced cell migration is dependent on vinculin and regulated by the membrane androgen receptor. FEBS J 279(7):1231–1242. https://doi.org/10.1111/j.1742-4658.2012.08515.x

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Y, Shi G, Zhang H, Xiong Q, Cheng F, Wang H et al (2021) Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway. Oncogene 40(35):5367–5378. https://doi.org/10.1038/s41388-021-01944-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mitre-Aguilar IB, Moreno-Mitre D, Melendez-Zajgla J, Maldonado V, Jacobo-Herrera NJ, Ramirez-Gonzalez V et al (2022) The role of glucocorticoids in breast cancer therapy. Curr Oncol 30(1):298–314. https://doi.org/10.3390/curroncol30010024

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lu YS, Lien HC, Yeh PY, Yeh KH, Kuo ML, Kuo SH et al (2005) Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors. World J Gastroenterol 11(40):6373–6380. https://doi.org/10.3748/wjg.v11.i40.6373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang H, Wang Y, Rayburn ER, Hill DL, Rinehart JJ, Zhang R (2007) Dexamethasone as a chemosensitizer for breast cancer chemotherapy: potentiation of the antitumor activity of adriamycin, modulation of cytokine expression, and pharmacokinetics. Int J Oncol 30(4):947–953. https://doi.org/10.3892/ijo.30.4.947

    Article  CAS  PubMed  Google Scholar 

  33. Wang H, Li M, Rinehart JJ, Zhang R (2004) Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy. Clin Cancer Res 10(5):1633–1644. https://doi.org/10.1158/1078-0432.CCR-0829-3

    Article  CAS  PubMed  Google Scholar 

  34. Skor MN, Wonder EL, Kocherginsky M, Goyal A, Hall BA, Cai Y et al (2013) Glucocorticoid receptor antagonism as a novel therapy for triple-negative breast cancer. Clin Cancer Res 19(22):6163–6172. https://doi.org/10.1158/1078-0432.CCR-12-3826

    Article  CAS  PubMed  Google Scholar 

  35. Maestro I, Boya P, Martinez A (2020) Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases. Expert Opin Ther Targets 24(3):231–243. https://doi.org/10.1080/14728222.2020.1730328

    Article  CAS  PubMed  Google Scholar 

  36. Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W et al (2008) Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res 68(18):7475–7483. https://doi.org/10.1158/0008-5472.CAN-08-1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang L, Li N, Xue Z, Liu LR, Li J, Huang X et al (2020) Synergistic therapeutic effect of combined PDGFR and SGK1 inhibition in metastasis-initiating cells of breast cancer. Cell Death Differ 27(7):2066–2080. https://doi.org/10.1038/s41418-019-0485-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu G, Honisch S, Liu G, Schmidt S, Pantelakos S, Alkahtani S et al (2015) Inhibition of SGK1 enhances mAR-induced apoptosis in MCF-7 breast cancer cells. Cancer Biol Ther 16(1):52–59. https://doi.org/10.4161/15384047.2014.986982

    Article  CAS  PubMed  Google Scholar 

  39. Tangir J, Bonafe N, Gilmore-Hebert M, Henegariu O, Chambers SK (2004) SGK1, a potential regulator of c-fms related breast cancer aggressiveness. Clin Exp Metastasis 21(6):477–483. https://doi.org/10.1007/s10585-004-4226-8

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Junjia Zhang & Takanori Ishida

  2. Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Junjia Zhang, Takashi Suzuki & Hironobu Sasano

  3. Department of Nursing, Faculty of Medical Science and Welfare, Tohoku Bunka Gakuen University, Sendai, Japan

    Yasuhiro Miki

  4. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Erina Iwabuchi & Takashi Suzuki

  5. The Cancer Hospital of the University of Chinese Academy of Sciences Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Junyao Xu

  6. Department of Breast Surgery, Hachinohe City Hospital, Aomori, Japan

    Ayako Kanai

  7. Department of Breast and Thyroid Surgical Oncology, Sagara Hospital, Kagoshima, Japan

    Yasuaki Sagara & Yoshiaki Rai

  8. Department of Pathology, Sagara Hospital, Kagoshima, Japan

    Yasuyo Ohi

  9. Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan

    Rin Yamaguchi

  10. JCHO Kurume General Hospital, Fukuoka, Japan

    Maki Tanaka

Authors
  1. Junjia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhiro Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erina Iwabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junyao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ayako Kanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuaki Sagara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuyo Ohi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshiaki Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rin Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takanori Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Takashi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hironobu Sasano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhiro Miki.

Ethics declarations

Conflict of interest

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: 2020-1-6, Sagara Hospital: 15-2, JCHO Kurume General Hospital: 148) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Miki, Y., Iwabuchi, E. et al. Induction of SGK1 via glucocorticoid-influenced clinical outcome of triple-negative breast cancer patients. Breast Cancer Res Treat 200, 323–335 (2023). https://doi.org/10.1007/s10549-023-06990-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-023-06990-4

Keywords

Search

Navigation