Breast Cancer Research and Treatment

, Volume 153, Issue 3, pp 625–634 | Cite as

The reciprocal association between mammographic breast density, hyaluronan synthesis and patient outcome

  • Amro Masarwah
  • Markku Tammi
  • Mazen Sudah
  • Anna Sutela
  • Sanna Oikari
  • Veli-Matti Kosma
  • Raija Tammi
  • Ritva Vanninen
  • Päivi Auvinen


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.


Breast cancer Hyaluronan Hyaluronan synthases Mammography Breast density 

List of Abbreviations


Mammographic breast density




Hyaluronan synthase


Human epidermal growth factor receptor 2


Very low density


Mixed density



Financial support was received from Kuopio University Hospital-VTR funds (MT, PA, RV, RT), EVO funding (Grant Nos. 5063525, 5063532) (AM, RV, AS), the University of Kuopio Foundation (AM), grants from Mauri and Sirkka Wiljasalo (AM) and the Paavo Koskinen foundation (AM), Spearhed Funds of the University of Eastern Finland (Cancer Center of Eastern Finland) (RV, PA, VMK, AM), Sigrid Juselius Foundation (RT, MT), and Cancer societies of Finland (RV, AM, MS). Authors are thankful for Tuomas Selander for kindly providing statistical advice for this manuscript.

Compliance with ethical standards

Conflicts of Interest

MT received travel imbursement and an honorarium for a lecture at Halozyme Inc., San Diego, CA. The remaining authors declare that they have no other potential competing interests.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Amro Masarwah
    • 1
    • 7
  • Markku Tammi
    • 2
  • Mazen Sudah
    • 1
    • 7
  • Anna Sutela
    • 1
    • 7
  • Sanna Oikari
    • 2
  • Veli-Matti Kosma
    • 3
    • 4
    • 5
    • 7
  • Raija Tammi
    • 2
  • Ritva Vanninen
    • 1
    • 4
    • 5
    • 7
  • Päivi Auvinen
    • 6
    • 7
  1. 1.Department of Clinical RadiologyKuopio University HospitalKuopioFinland
  2. 2.Department of Medicine, Institute of BiomedicineUniversity of Eastern FinlandKuopioFinland
  3. 3.Department of PathologyKuopio University HospitalKuopioFinland
  4. 4.Biocenter Kuopio and Cancer Center of Eastern FinlandUniversity of Eastern FinlandKuopioFinland
  5. 5.Institute of Clinical MedicineUniversity of Eastern FinlandKuopioFinland
  6. 6.Department of OncologyKuopio University HospitalKuopioFinland
  7. 7.Kuopio University HospitalKYSFinland

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