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Gene expression of adipokines and adipokine receptors in the tumor microenvironment: associations of lower expression with more aggressive breast tumor features

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

Abstract

Purpose

Limited epidemiologic data are available on the expression of adipokines leptin (LEP) and adiponectin (ADIPOQ) and adipokine receptors (LEPR, ADIPOR1, ADIPOR2) in the breast tumor microenvironment (TME). The associations of gene expression of these biomarkers with tumor clinicopathology are not well understood.

Methods

NanoString multiplexed assays were used to assess the gene expression levels of LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 within tumor tissues among 162 Black and 55 White women with newly diagnosed breast cancer. Multivariate mixed effects models were used to estimate associations of gene expression with breast tumor clinicopathology (overall and separately among Blacks).

Results

Black race was associated with lower gene expression of LEPR (P = 0.002) and ADIPOR1 (P = 0.01). Lower LEP, LEPR, and ADIPOQ gene expression were associated with higher tumor grade (P = 0.0007, P < 0.0001, and P < 0.0001, respectively) and larger tumor size (P < 0.0001, P = 0.0005, and P < 0.0001, respectively). Lower ADIPOQ expression was associated with ER- status (P = 0.0005), and HER2-enriched (HER2-E; P = 0.0003) and triple-negative (TN; P = 0.002) subtypes. Lower ADIPOR2 expression was associated with Ki67+ status (P = 0.0002), ER- status (P < 0.0001), PR- status (P < 0.0001), and TN subtype (P = 0.0002). Associations of lower adipokine and adipokine receptor gene expression with ER-, HER2-E, and TN subtypes were confirmed using data from The Cancer Genome Atlas (P-values < 0.005).

Conclusion

These findings suggest that lower expression of ADIPOQ, ADIPOR2, LEP, and LEPR in the breast TME might be indicators of more aggressive breast cancer phenotypes. Validation of these findings are warranted to elucidate the role of the adipokines and adipokine receptors in long-term breast cancer prognosis.

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Abbreviations

ADIPOQ:

Adiponectin

ADIPOR1:

Adiponectin receptor 1

ADIPOR2:

Adiponectin receptor 2

ANOVA:

Analysis of variance

BC:

Breast cancer

BMI:

Body mass index

DBBR:

Data Bank and Biorepository

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

HER2-E:

Non-luminal HER2-enriched subtype

IGF-1:

Insulin-like growth factor 1

IHC:

Immunohistochemistry

IRS1:

Insulin receptor substrate 1

JAK/STAT:

Janus kinase-signal transducer and activator of transcription

LEP:

Leptin

LEPR:

Leptin receptor

MAPK:

Mitogen-activated protein kinase

PR:

Progesterone receptor

SD:

Standard deviation

SOCS3:

Suppressor of cytokine signaling 3

TCGA:

The Cancer Genome Atlas

TN:

Triple-negative subtype

TNF-α:

Tumor necrosis factor alpha

WCHS:

Women’s Circle of Health Study

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Acknowledgements

We are sincerely appreciative of the breast cancer advocates, community partners, and all of the women who generously donated their time to participate in the study. We are equally grateful to the highly motivated, hardworking research personnel of the Women’s Circle of Health Study at the Rutgers School of Public Health, Rutgers Cancer Institute of New Jersey, Roswell Park Comprehensive Cancer Center, Mount Sinai School of Medicine (now Icahn School of Medicine at Mount Sinai), and the New Jersey State Cancer Registry.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: P01CA151135 (awarded to C.B. Ambrosone), P30CA072720 (awarded to S. Libutti), R01CA100598 (awarded to C.B. Ambrosone), R01CA185623 (awarded to E.V. Bandera, K. Demissie, and C.C. Hong), K01CA193527 (awarded to A.A.M. Llanos), and K08CA172722 (awarded to C. Omene). Research in this publication was also supported by the U.S. Army Medical Research and Development Command under award number DAMD‐17‐01‐1‐0334 (awarded to D.H. Bovbjerg), the Breast Cancer Research Foundation (awarded to C.B. Ambrosone and C.C. Hong), and a gift from the Philip L. Hubbell Family (awarded to K. Demissie). Tumor samples were received, processed and tracked under the auspices of the Roswell Park Comprehensive Cancer Center Data Bank and BioRepository Shared Resource, with funding from NCI-CCSG P30CA16056. Services, results and/or products in support of this research project were generated using the Rutgers Cancer Institute of New Jersey Biomedical Informatics Shared Resource (P30CA072720-5917) and the Biospecimen Repository and Histopathology Service Shared Resource (P30CA072720-5919). The New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey Department of Health, is funded by the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute under contract HHSN261201300021I and control No. N01-PC-2013-00021, the National Program of Cancer Registries (NPCR), Centers for Disease Control and Prevention under grant NU5U58DP006279-02-00 as well as the State of New Jersey and the Rutgers Cancer Institute of New Jersey.

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Authors and Affiliations

  1. Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA

    Adana A. M. Llanos, John B. Aremu, Yong Lin & Elisa V. Bandera

  2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Adana A. M. Llanos, Amartya Singh, Hossein Khiabanian, Yong Lin, Coral Omene, Shridar Ganesan, David J. Foran & Elisa V. Bandera

  3. Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Song Yao, Angela R. Omilian, Chi-Chen Hong & Christine B. Ambrosone

  4. Department of Physics and Astronomy, School of Graduate Studies, Rutgers University, New Brunswick, NJ, USA

    Amartya Singh

  5. Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Hossein Khiabanian & David J. Foran

  6. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Coral Omene & Shridar Ganesan

  7. Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Thaer Khoury

  8. Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Shridar Ganesan

  9. Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Michael J. Higgins

  10. Department of Epidemiology and Biostatistics, SUNY Downstate Health Sciences University School of Public Health, Brooklyn, NY, USA

    Kitaw Demissie

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  1. Adana A. M. Llanos
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Corresponding author

Correspondence to Adana A. M. Llanos.

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The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Institutional Review Boards of all participating institutions. 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.

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Informed consent was obtained from all individual participants included in the study (prior to enrollment in the study).

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This article does not contain any studies with animals performed by any of the authors.

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Llanos, A.A.M., Yao, S., Singh, A. et al. Gene expression of adipokines and adipokine receptors in the tumor microenvironment: associations of lower expression with more aggressive breast tumor features. Breast Cancer Res Treat 185, 785–798 (2021). https://doi.org/10.1007/s10549-020-05972-0

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