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High extent of O-GlcNAcylation in breast cancer cells correlates with the levels of HAS enzymes, accumulation of hyaluronan, and poor outcome

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

Abstract

Purpose

Obesity and oversupply of glucose, e.g., due to nutritional factors may shape the tumor microenvironment favorable for tumor progression. O-GlcNAcylation, a reversible modification of intracellular proteins, influences on several cellular functions and is connected to many diseases including cancer. Glycosaminoglycan hyaluronan (HA) enhances tumor progression and in breast cancer HA accumulation associates strongly with poor outcome. In vitro studies have suggested that O-GlcNAcylation may enhance HA synthesis. The aim of this study was to investigate the correlations between O-GlcNAcylation, HA-related parameters, and disease outcome in a clinical breast cancer material consisting of 278 breast cancer cases.

Methods

In microscopic analyses, O-GlcNAc staining of the breast carcinoma cells was evaluated in several randomly picked high-power fields of each section. The extent of cytoplasmic O-GlcNAc staining was graded as either low or high according to the intensity of the staining and the percentage of stained cells. The extent of nuclear O-GlcNAc staining was categorized as either low or high according to the percentage of stained nuclei.

Results

A high extent of both cytoplasmic and nuclear O-GlcNAcylation correlated with an increased relapse rate, development of distant metastases, and poor outcome. A high extent of cytoplasmic O-GlcNAcylation correlated also with the accumulation of all hyaluronan synthase (HAS1-3) proteins and with a large amount of HA in the tumor stroma. In addition, a high extent of nuclear O-GlcNAcylation associated with obesity.

Conclusions

The results suggest a mechanistic association between increased O-GlcNAcylation and HA synthesis, leading to a HA-rich microenvironment favorable for breast cancer progression.

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Abbreviations

FDG-PET:

18F-fluorodeoxyglucose-positron emission tomography

HBP:

Hexosamine biosynthetic pathway

UDP-GlcNAc:

Uridine diphosphate N-acetylglucosamine

HA:

Hyaluronan

HAS:

Hyaluronan synthase

UDP-GlcUA:

Uridine diphosphate glucuronic acid

HER2:

Human epidermal growth factor receptor 2

OGT:

O-GlcNAc transferase

OGA, MGEA5:

O-GlcNAcase

PB:

Phosphate buffer

BSA:

Bovine serum albumin

ER:

Estrogen receptor

PR:

Progesterone receptor

BMI:

Body mass index

DFS:

Disease-free survival

OS:

Overall survival

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Acknowledgments

We thank Kari Kotikumpu and Eija Rahunen (Institute of Biomedicine, Anatomy, University of Eastern Finland, Finland) for technical help with O-GlcNAc immunostaining, Tuomas Selander (Science Service Center, Kuopio University Hospital, Finland) for assistance with the statistical analyses, and Ewen MacDonald for English language editing.

Funding

This study was supported by the Special Government Funding (EVO/VTR) of Kuopio University Hospital (Grant Nos. 5654132 and 5053101) and a Grant from Cancer Society of North Savo. The funders were not involved in the collection, management, or analysis of the data.

Author information

Authors and Affiliations

  1. Cancer Center, Kuopio University Hospital, P.O. Box 100, 70029, Kuopio, Finland

    Satu Tiainen & Päivi Auvinen

  2. Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Satu Tiainen & Päivi Auvinen

  3. Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Sanna Oikari, Markku Tammi, Kirsi Rilla & Raija Tammi

  4. Clinical Pathology and Forensic Medicine, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Kirsi Hämäläinen & Veli-Matti Kosma

  5. Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Kirsi Hämäläinen & Veli-Matti Kosma

  6. Clinical Pathology, Imaging Center, Kuopio University Hospital, P.O. Box 100, 70029, Kuopio, Finland

    Kirsi Hämäläinen & Veli-Matti Kosma

Authors
  1. Satu Tiainen
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  2. Sanna Oikari
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Correspondence to Satu Tiainen.

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The authors declare that they have no conflict of interest.

Ethical approval

Ethical approval for this study was provided by the Ethics Committee of the University of Eastern Finland and by the National Supervisory Authority for Welfare and Health. The execution of this study complies with the current laws of Finland.

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Tiainen, S., Oikari, S., Tammi, M. et al. High extent of O-GlcNAcylation in breast cancer cells correlates with the levels of HAS enzymes, accumulation of hyaluronan, and poor outcome. Breast Cancer Res Treat 160, 237–247 (2016). https://doi.org/10.1007/s10549-016-3996-4

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  • DOI: https://doi.org/10.1007/s10549-016-3996-4

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