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



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.


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.


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.


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.


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



β2-Adrenergic receptor


Confidence interval


Breast cancer-specific survival


Estrogen receptor


Human epidermal growth factor 2


Hazard ratio


Programmed death ligand 1


Progesterone receptor


Tumor-infiltrating lymphocyte



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


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)


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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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