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Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status: Regulation of hyaluronan/HAS2/CD44 and specific matrix effectors
Univ Patras, Dept Chem, Lab Biochem, Biochem Biochem Anal & Matrix Pathobiol Res Grp, GR-26110 Patras, Greece.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0001-9818-4052
Univ Patras, Dept Chem, Lab Biochem, Biochem Biochem Anal & Matrix Pathobiol Res Grp, GR-26110 Patras, Greece.
Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA;Thomas Jefferson Univ, Kimmel Canc Ctr, Canc Cell Biol & Signaling Program, Philadelphia, PA 19107 USA.
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2019 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 78-79, p. 118-138Article in journal (Refereed) Published
Abstract [en]

The malignant phenotype of various cancers is linked to enhanced expression of hyaluronan, a proangiogenic glycosaminoglycan whose expression is suppressed by 4-methylumbelliferone (4-MU), a non-toxic oral agent used as a dietary supplement to improve health and combat prostate cancer. In this study, we investigated the role of 4-MU in mammary carcinoma cells with distinct malignant phenotypes and estrogen receptor (ER) status, a major prognostic factor in the clinical management of breast cancers. We focused on two breast cancer cell lines, the low metastatic and ER alpha+ MCF-7 cells, and the highly-aggressive and ER alpha-MDA-MB-231 cells. Treatment with 4-MU caused a dose-dependent decrease of hyaluronan accumulation in the extracellular matrix as well as within the breast cancer cells, most prevalent in cells lacking ER alpha. This decrease in hyaluronan was accompanied by suppression of Hyaluronan Synthase 2 (HAS2), the major enzyme responsible for the synthesis of hyaluronan, and by induction of hyaluronidases (HYALs) -1 and -2. Moreover, 4-MU induced intense phenotypic changes and substantial loss of CD44, a major hyaluronan receptor, from cell protrusions. Importantly, 4-MU evoked differential effects depending on the absence or presence of ER alpha. Only the ER alpha+ cells showed signs of apoptosis, as determined by cleaved PARP-1, and anoikis as shown by concurrent loss of E-cadherin and beta-catenin. Interestingly, 4-MU significantly reduced migration, adhesion and invasion of ER alpha- breast cancer cells, and concurrently reduced the expression and activity of several matrix degrading enzymes and pro-inflammatory molecules with tumor-promoting functions. Collectively, our findings suggest that 4-MU could represent a novel therapeutic for specific breast cancer subtypes with regard to their ER status via suppression of hyaluronan synthesis and regulation of HAS2, CD44, matrix-degrading enzymes and inflammatory mediators. 

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2019. Vol. 78-79, p. 118-138
Keywords [en]
Hyaluronan, CD44, Hyaluronan synthase, 4-Methylumbelliferone, Breast cancer, Estrogen receptors
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-386170DOI: 10.1016/j.matbio.2018.04.007ISI: 000468707600009PubMedID: 29673760OAI: oai:DiVA.org:uu-386170DiVA, id: diva2:1327979
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved

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Heldin, Paraskevi

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