title: The reciprocal association between mammographic breast density, hyaluronan synthesis and patient outcome.
abstract: Low mammographic breast density (MBD) and increased hyaluronan (HA) synthesis have been shown to have adverse effects on breast cancer prognosis. We aimed at elucidating the background of risk associated with mammographic characteristics, MBD and HA and its synthesizing isoforms in an attempt to uncover potential underlying biological mechanisms. MBD and mammographic characteristics of 270 patients were classified according to percentile density (very low density VLD, ≤25 %; mixed density MID, >25 %) and the BI-RADS 5th edition lexicon. Breast density and mammographic features were correlated with the localization and expression of HA, CD44, and HAS1-3 isoforms, and their combined effect on patients' survivals was explored. VLD showed an increased level of HA-positive carcinoma cells and stromal HA, HAS2, and HAS3. Tumors presenting as masses had more HA-positive carcinoma cells and more stromal HAS2 and HAS3. Indistinct margin tumors showed more stromal HA and HAS3. Patients who combined both VLD breasts with either high HA in carcinoma cells or stroma showed a worse prognosis compared to low levels (carcinoma cells 58.0 vs. 80.5 %, p = 0.001; stroma 64.2 vs. 79.6 %, p = 0.017), while no similar HA-related effect was observed in MID breasts. Our findings suggest a strong reciprocal relationship between low MBD and HA expression and synthesis. The expression of both factors simultaneously leads to an especially adverse prognostic effect which might have an impact on treatment decision in the future. Moreover, HA around cancer cells may inhibit chemotherapy agents and antibody treatments from reaching cancer cells.
authors.affiliation: Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland. amro.masarwah@kuh.fi.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland. amro.masarwah@kuh.fi.
authors.forename: Amro
authors.initials: A
authors.lastname: Masarwah
authors.affiliation: Department of Medicine, Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Tammi
authors.affiliation: Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland.
authors.forename: Mazen
authors.initials: M
authors.lastname: Sudah
authors.affiliation: Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sutela
authors.affiliation: Department of Medicine, Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Oikari
authors.affiliation: Department of Pathology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.|Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Department of Medicine, Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Tammi
authors.affiliation: Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland.|Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.|Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1E, P.O. Box 1627, 70211, Kuopio, Finland.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland.
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
authors.affiliation: Department of Oncology, Kuopio University Hospital, Puijonlaaksontie 2, 70210, Kuopio, Finland.|Kuopio University Hospital, P.O. Box PL 100, 70029, KYS, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Auvinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071060:Breast Density; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D047368:Tumor Burden
chemical_list: D014453:Glucuronosyltransferase; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Breast cancer; Breast density; Hyaluronan; Hyaluronan synthases; Mammography