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β2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer

  • Sasagu KurozumiEmail author
  • Kyoichi Kaira
  • Hiroshi Matsumoto
  • Tomoko Hirakata
  • Takehiko Yokobori
  • Kenichi Inoue
  • Jun Horiguchi
  • Ayaka Katayama
  • Hiromi Koshi
  • Akira Shimizu
  • Tetsunari Oyama
  • Erica K. Sloan
  • Masafumi Kurosumi
  • Takaaki Fujii
  • Ken Shirabe
Preclinical study

Abstract

Purpose

Antitumor immunity plays an important role in the progression of breast cancer. β2-adrenergic receptor (β2AR) was found to regulate the antitumor immune response and breast cancer progression in preclinical studies. To understand the clinical role of β2AR in cancer progression, we investigated the clinicopathological and prognostic significance of β2AR expression in invasive breast cancer.

Methods

β2AR levels in breast tumors were evaluated by immunohistochemistry in a well-characterized patient cohort with long-term follow-up (n = 278). We evaluated the relationship of β2AR expression to patient survival and clinicopathological factors, including immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. Breast cancer-specific survival was compared between high- and low-β2AR expression groups.

Results

Although β2AR was not related to clinicopathological factors across the whole cohort, high β2AR was significantly related to PD-L1 negativity in estrogen receptor (ER)-negative patients. Tumors with high β2AR tended to have low TIL grade, and high β2AR was an independent prognostic factor for reduced survival in ER-negative patients.

Conclusions

β2AR is an independent poor prognostic factor in ER-negative breast cancer. The findings suggest that tumor β2AR regulates immune checkpoint activity, which may have therapeutic implications for patients with ER-negative breast cancer.

Keywords

Invasive breast cancer ER-negative β2-Adrenergic receptor Tumor-infiltrating lymphocytes PD-L1 Immune checkpoint 

Abbreviations

β2AR

β2-Adrenergic receptor

CI

Confidence interval

CSS

Breast cancer-specific survival

ER

Estrogen receptor

HER2

Human epidermal growth factor 2

HR

Hazard ratio

PD-L1

Programmed death ligand 1

PgR

Progesterone receptor

TIL

Tumor-infiltrating lymphocyte

Notes

Acknowledgements

We gratefully acknowledge the work of our research technician, Kumiko Sudo, in the Department of Pathology, Saitama Cancer Center.

Funding

EKS is supported by the Australian National Health and Medical Research Council (Grant Number: APP1147498).

Compliance with ethical standards

Conflict of interest

TY has received research grants from Ono Pharmaceutical Co., Ltd., CHUGAI Pharmaceutical Co., Ltd., and Memolead CO. KI has received a speaker honorarium from Eisai Co., Ltd., CHUGAI Pharmaceutical Co., Ltd., Pfizer Inc. KI has received research grants from Novartis Pharma K.K., Pfizer Inc., CHUGAI Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., PAREXEL/Puma Biotechnology, Merck Sharp & Dohme Ltd., Bayer Yakuhin, Ltd., Eli Lilly and Company, and Eisai Co., Ltd. EKS is a member of the scientific advisory board of Cygnal Therapeutics. MK received a speaker honorarium CHUGAI Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd. KS has received research grants from CHUGAI Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd. The other authors declare that they have no conflicts of interest.

Research involving human and animal participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

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

Supplementary material

10549_2019_5341_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 19 kb)

References

  1. 1.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717Google Scholar
  2. 2.
    Liedtke C, Mazouni C, Hess KR et al (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275–1281CrossRefGoogle Scholar
  3. 3.
    Kurozumi S, Joseph C, Sonbul S et al (2018) Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer. Breast Cancer Res Treat 172:61–68CrossRefGoogle Scholar
  4. 4.
    Kurozumi S, Joseph C, Sonbul S et al (2018) Clinical and biological roles of Kelch-like family member 7 in breast cancer: a marker of poor prognosis. Breast Cancer Res Treat 170:525–533CrossRefGoogle Scholar
  5. 5.
    Kurozumi S, Yamaguchi Y, Hayashi S et al (2016) Prognostic value of the ubiquitin ligase carboxyl terminus of the Hsc70-interacting protein in postmenopausal breast cancer. Cancer Med 5:1873–1882CrossRefGoogle Scholar
  6. 6.
    Baker JG, Hill SJ, Summers RJ (2011) Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling. Trends Pharmacol Sci 32:227–234CrossRefGoogle Scholar
  7. 7.
    Renz BW, Takahashi R, Tanaka T et al (2018) β2 Adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33:75–90CrossRefGoogle Scholar
  8. 8.
    Walker AK, Martelli D, Ziegler AI et al (2019) Circulating epinephrine is not required for chronic stress to enhance metastasis. Psychoneuroendocrinology 99:191–195CrossRefGoogle Scholar
  9. 9.
    Masur K, Niggemann B, Zanker KS, Entschladen F (2001) Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 61:2866–2869Google Scholar
  10. 10.
    Chang A, Le CP, Walker AK et al (2016) β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav Immun 57:106–115CrossRefGoogle Scholar
  11. 11.
    Creed SJ, Le CP, Hassan M et al (2015) β2-Adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Res 17:145CrossRefGoogle Scholar
  12. 12.
    Botteri E, Munzone E, Rotmensz N et al (2013) Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat 140:567–575CrossRefGoogle Scholar
  13. 13.
    Le CP, Nowell CJ, Kim-Fuchs C et al (2016) Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun 7:10634CrossRefGoogle Scholar
  14. 14.
    Melhem-Bertrandt A, Chavez-Macgregor M, Lei X et al (2011) Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29:2645–2652CrossRefGoogle Scholar
  15. 15.
    Palm D, Lang K, Niggemann B et al (2006) The norepinephrine-driven metastasis development of PC–3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer 118:2744–2749CrossRefGoogle Scholar
  16. 16.
    Powe DG, Voss MJ, Habashy HO et al (2011) Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study. Breast Cancer Res Treat 130:457–463CrossRefGoogle Scholar
  17. 17.
    Hara MR, Kovacs JJ, Whalen EJ et al (2011) A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477:349–353CrossRefGoogle Scholar
  18. 18.
    Liu H, Wang C, Xie N et al (2018) Activation of adrenergic receptor β2 promotes tumor progression and epithelial mesenchymal transition in tongue squamous cell carcinoma. Int J Mol Med 41:147–154Google Scholar
  19. 19.
    Sanders VM (2012) The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain Behav Immun 26:195–200CrossRefGoogle Scholar
  20. 20.
    Qiao G, Bucsek MJ, Winder NM et al (2019) β-Adrenergic signaling blocks murine CD8 + T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress. Cancer Immunol Immunother 68:11–22CrossRefGoogle Scholar
  21. 21.
    Nissen MD, Sloan EK, Mattarollo SR (2018) β-Adrenergic signaling impairs antitumor CD8 + T-cell responses to B-cell lymphoma immunotherapy. Cancer Immunol Res 6:98–109CrossRefGoogle Scholar
  22. 22.
    Kurozumi S, Matsumoto H, Kurosumi M et al (2019) Prognostic significance of tumour-infiltrating lymphocytes for oestrogen receptor-negative breast cancer without lymph node metastasis. Oncol Lett 17:2647–2656Google Scholar
  23. 23.
    Darvin P, Toor SM, Sasidharan Nair V et al (2018) Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 50:165CrossRefGoogle Scholar
  24. 24.
    Kurozumi S, Matsumoto H, Hayashi Y et al (2017) Power of PgR expression as a prognostic factor for ER-positive/HER2-negative breast cancer patients at intermediate risk classified by the Ki67 labeling index. BMC Cancer 17:354CrossRefGoogle Scholar
  25. 25.
    Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271CrossRefGoogle Scholar
  26. 26.
    Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920CrossRefGoogle Scholar
  27. 27.
    Kaira K, Kamiyoshihara M, Kawashima O et al (2019) Prognostic impact of β2 adrenergic receptor expression in surgically resected pulmonary pleomorphic carcinoma. Anticancer Res 39:395–403CrossRefGoogle Scholar
  28. 28.
    Yazawa T, Kaira K, Shimizu K et al (2016) Prognostic significance of β2-adrenergic receptor expression in non-small cell lung cancer. Am J Transl Res 8:5059–5070Google Scholar
  29. 29.
    Takahashi K, Kaira K, Shimizu A et al (2016) Clinical significance of β2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma. Tumour Biol 37:13885–13892CrossRefGoogle Scholar
  30. 30.
    Shimizu A, Kaira K, Mori K et al (2016) Prognostic significance of β2-adrenergic receptor expression in malignant melanoma. Tumour Biol 37:5971–5978CrossRefGoogle Scholar
  31. 31.
    Zhang ZF, Feng XS, Chen H et al (2016) Prognostic significance of synergistic hexokinase-2 and beta2-adrenergic receptor expression in human hepatocelluar carcinoma after curative resection. BMC Gastroenterol 16:57CrossRefGoogle Scholar
  32. 32.
    Kurozumi S, Fujii T, Matsumoto H et al (2017) Significance of evaluating tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer. Med Mol Morphol 50:185–194CrossRefGoogle Scholar
  33. 33.
    Kurozumi S, Inoue K, Matsumoto H et al (2019) Prognostic utility of tumor-infiltrating lymphocytes in residual tumor after neoadjuvant chemotherapy with trastuzumab for HER2-positive breast cancer. Sci Rep 9:1583CrossRefGoogle Scholar
  34. 34.
    Bucsek MJ, Qiao G, MacDonald CR et al (2017) β-Adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res 77:5639–5651CrossRefGoogle Scholar
  35. 35.
    Estrada LD, Ağaç D, Farrar JD (2016) Sympathetic neural signaling via the β2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function. Eur J Immunol 46:1948–1958CrossRefGoogle Scholar
  36. 36.
    Qin JF, Jin FJ, Li N et al (2015) Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Rep 48:295–300CrossRefGoogle Scholar
  37. 37.
    Sloan EK, Priceman SJ, Cox BF et al (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70:7042–7052CrossRefGoogle Scholar
  38. 38.
    Wu H, Chen J, Song S et al (2016) β2-Adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats. Sci Rep 6:24548CrossRefGoogle Scholar
  39. 39.
    Denkert C, von Minckwitz G, Darb-Esfahani S et al (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40–50CrossRefGoogle Scholar
  40. 40.
    Rody A, Holtrich U, Pusztai L et al (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11:R15CrossRefGoogle Scholar
  41. 41.
    Watanabe T, Hida AI, Inoue N et al (2018) Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers. Breast Cancer Res Treat 168:135–145CrossRefGoogle Scholar
  42. 42.
    Biswas SK (2015) Metabolic reprogramming of immune cells in cancer progression. Immunity 43:435–449CrossRefGoogle Scholar
  43. 43.
    Repasky EA, Eng J, Hylander BL (2015) Stress, metabolism and cancer: integrated pathways contributing to immune suppression. Cancer J 21:97–103CrossRefGoogle Scholar
  44. 44.
    Ostroumov D, Fekete-Drimusz N, Saborowski M, Kühnel F, Woller N (2018) CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci 75:689–713CrossRefGoogle Scholar
  45. 45.
    Schmid P, Adams S, Rugo HS et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108–2121CrossRefGoogle Scholar
  46. 46.
    Li Z, Qiu Y, Lu W, Jiang Y, Wang J (2018) Immunotherapeutic interventions of triple negative breast cancer. J Transl Med 16:147CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sasagu Kurozumi
    • 1
    • 2
    Email author
  • Kyoichi Kaira
    • 3
  • Hiroshi Matsumoto
    • 2
  • Tomoko Hirakata
    • 1
  • Takehiko Yokobori
    • 4
  • Kenichi Inoue
    • 5
  • Jun Horiguchi
    • 6
  • Ayaka Katayama
    • 7
  • Hiromi Koshi
    • 7
  • Akira Shimizu
    • 8
  • Tetsunari Oyama
    • 7
  • Erica K. Sloan
    • 9
  • Masafumi Kurosumi
    • 10
  • Takaaki Fujii
    • 1
  • Ken Shirabe
    • 1
  1. 1.Department of General Surgical ScienceGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Division of Breast SurgerySaitama Cancer CenterSaitamaJapan
  3. 3.Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical CenterSaitama Medical UniversitySaitamaJapan
  4. 4.Department of Innovative Cancer ImmunotherapyGunma UniversityMaebashiJapan
  5. 5.Division of Breast OncologySaitama Cancer CenterSaitamaJapan
  6. 6.Department of Breast SurgeryInternational University of Health and WelfareChibaJapan
  7. 7.Department of Diagnostic PathologyGunma University Graduate School of MedicineMaebashiJapan
  8. 8.Department of DermatologyGunma University Graduate School of MedicineMaebashiJapan
  9. 9.Drug Discovery Biology Theme, Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia
  10. 10.Department of PathologySaitama Cancer CenterSaitamaJapan

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