title: Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival.
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.
authors: Department of Oncology, Cancer Center, Kuopio University Hospital, P.O. Box 100, 70029, Kuopio, Finland, paivi.auvinen@kuh.fi.
authors: Päivi
authors: P
authors: Auvinen
authors: Kirsi
authors: K
authors: Rilla
authors: Ritva
authors: R
authors: Tumelius
authors: Markku
authors: M
authors: Tammi
authors: Reijo
authors: R
authors: Sironen
authors: Ylermi
authors: Y
authors: Soini
authors: Veli-Matti
authors: VM
authors: Kosma
authors: Arto
authors: A
authors: Mannermaa
authors: Jukka
authors: J
authors: Viikari
authors: Raija
authors: R
authors: Tammi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000401:mortality; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009765:Obesity / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology*; D013534:Survival; D016019:Survival Analysis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014453:Glucuronosyltransferase; D018960:Hyaluronan Receptors; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C497483:CD44 protein, human; C523794:HAS1 protein, human; C101754:HAS2 protein, human; C105458:HAS3 protein, human; C508053:ERBB2 protein, human