Hyaluronan in Breast Cancer: Correlations With Nitric Oxide Synthases and Tyrosine Nitrosylation
Peeter Karihtala 1*, Ylermi Soini 1, Päivi Auvinen 1, Raija Tammi 1, Markku Tammi 1 and Veli-Matti Kosma 1
1 Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland (PK); Institute of Clinical Medicine, Pathology and Forensic Medicine (YS,V-MK) and Institute of Biomedicine, Anatomy (RT,MT), University of Kuopio, Kuopio, Finland; and Department of Clinical Pathology (YS,V-MK) and Department of Oncology (PA), Kuopio University Hospital, Kuopio, Finland
* To whom correspondence should be addressed. E-mail: peeter.karihtala{at}oulu.fi.
Submitted on May 2, 2007
Accepted on 20 July 2007
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Abstract |
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Reactive oxygen species (ROS), including nitric oxide (NO•) are associated with all steps of carcinogenesis. Hyaluronan (HA), a high-molecular mass glycosaminoglycan overexpressed in a variety of human malignancies has also ROS-scavenging properties. We studied histochemically the level of HA in breast carcinoma cells and their stroma and compared with the expression of NO• synthases (NOS), major antioxidant enzymes, and nitrotyrosine. We also assessed whether the level of HA correlates with traditional prognostic factors of breast cancer, and survival. Stromal HA level was moderate or high in all the samples studied (n=185), and 84% of the lesions showed HA-positive carcinoma cells. Intense stromal HA signal associated with high nNOS expression (p=0.009), while tumor-cell associated HA correlated inversely with nitrotyrosine expression (p=0.027). Of the traditional prognostic factors, tumor-cell associated HA correlated with poor differentiation (p=0.011) and high stromal HA levels associated with aggressive features of the carcinomas such as large primary tumor (p=0.002), poor differentiation (p=0.019) and estrogen (p=0.012) and progesterone receptor negativity (p=0.009). High stromal HA level predicted also significantly poorer survival. The strong positive correlation between nNOS and stromal HA could reflect NO• -stimulated synthesis of HA, an extracellular matrix alteration that favors breast cancer progression. Furthermore, it is suggested that while acting as a scavenger of NO• derived radicals, cell-associated HA undergoes partial fragmentation, release from receptors, further degradation in lysosomes, and thus becomes undetectable in histological sections.
Key Words:
antioxidant enzymes, hyaluronic acid, nitric oxide, nitric oxide synthases, nitrotyrosine, reactive oxygen species
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