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Hyaluronan synthases (HAS1–3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival

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Abstract

Accumulation of hyaluronan (HA) in pericellular stroma and carcinoma cells is predictive of unfavorable patient prognosis in many epithelial cancers. However, it is not known whether the HA originates from carcinoma or stromal cells, or whether increased expression of hyaluronan synthase proteins (HAS1–3) contributes to HA accumulation. In this study, localization and expression of HAS1–3 were evaluated immunohistochemically in 278 cases of human breast cancer, and correlated with prognostic factors and patient outcome. Both carcinoma cells and stromal cells were HAS-positive. In carcinoma cells, HAS1 and HA stainings correlated with each other, and HAS1 associated with estrogen receptor negativity, HER2 positivity, high relapse rate, and short overall survival. In stromal cells, the staining levels of all HAS isoforms correlated with the stromal HA staining, stromal cell CD44, high relapse rate, and short overall survival of the patients. In addition, expression levels of stromal HAS1 and HAS2 were related to obesity, large tumor size, lymph node positivity, and estrogen receptor negativity. Thus, stromal HAS1 and HAS3 were independent prognostic factors in the multivariate analysis. The data suggest that increased levels of HAS enzymes contribute to the accumulation of HA in breast cancer, and that HA is synthesized in carcinoma cells and stromal cells. The study also indicates that HAS enzyme levels are related to tumor aggressiveness and poor patient outcome representing potential targets for therapy.

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Abbreviations

HA:

Hyaluronan

Has, HAS:

Hyaluronan synthase gene and protein

bHABC:

Biotinylated hyaluronan binding complex

HR:

Hazard ratio

TSG-6:

Tumor necrosis factor alpha stimulated gene-6

IαI:

Inter alpha inhibitor

UDP:

Uridine diphosphate

RAR:

Retinoic acid receptor

STAT:

Signal transducer and activator of transcription

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

CREB:

cAMP response element binding protein

CISH:

Chromogenic in situ hybridization

BMI:

Body mass index

GlcUA:

Glucuronic acid

GlcNAc:

N-acetyl-glucosamine

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Acknowledgments

This study has been supported by Special Government Funding (EVO) of Kuopio University Hospital (PA, VMK, MT), Cancer Center of University of Eastern Finland (PA, VMK, MT, RT), Sigrid Juselius Foundation (RT, MT), Northern Savo Cancer Foundation (KR).We thank Helena Kemiläinen, Eija Rahunen, and Kari Kotikumpu for their assistance in the laboratory.

Conflict of interest

The authors declare that they have no conflict of interest, neither financial nor personal.

Ethical standards

The permission for this study was provided by the ethics committee of University of Eastern Finland and by the national authority—VALVIRA.

Author information

Authors and Affiliations

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

    Päivi Auvinen

  2. Department of Anatomy, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

    Kirsi Rilla, Ritva Tumelius, Markku Tammi, Jukka Viikari & Raija Tammi

  3. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

    Reijo Sironen, Ylermi Soini, Veli-Matti Kosma & Arto Mannermaa

  4. Biocenter Kuopio and Cancer Center of Easter Finland, University of Eastern Finland, Kuopio, Finland

    Reijo Sironen, Ylermi Soini, Veli-Matti Kosma & Arto Mannermaa

  5. Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

    Reijo Sironen, Ylermi Soini, Veli-Matti Kosma & Arto Mannermaa

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  1. Päivi Auvinen
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  2. Kirsi Rilla
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Correspondence to Päivi Auvinen.

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Auvinen, P., Rilla, K., Tumelius, R. et al. Hyaluronan synthases (HAS1–3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res Treat 143, 277–286 (2014). https://doi.org/10.1007/s10549-013-2804-7

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  • DOI: https://doi.org/10.1007/s10549-013-2804-7

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