Tumor-suppressive functions of 4-MU on breast cancer cells of different ER status: Regulation of hyaluronan/HAS2/CD44 and specific matrix effectors

• Published in: Matrix biology 2019-05, Vol.78-79, p.118-138
• Main Authors: Karalis, Theodoros T., Heldin, Paraskevi, Vynios, Demitrios H., Neill, Thomas, Buraschi, Simone, Iozzo, Renato V., Karamanos, Nikos K., Skandalis, Spyros S.
• Format: Article
• Language: English
• Subjects: 4-Methylumbelliferone; Angiogenesis; Anoikis; Apoptosis; Breast cancer; Carcinoma; CD44; CD44 antigen; Dietary supplements; E-cadherin; Enzymes; Estrogen receptors; Extracellular matrix; Hyaluronan; Hyaluronan synthase; Hyaluronic acid; Inflammation; Mammary gland; Metastases; Phenotypes; Prostate cancer; Tumor cell lines; β-Catenin
• ISSN: 0945-053X; 1569-1802; 1569-1802
• DOI: 10.1016/j.matbio.2018.04.007

The malignant phenotype of various cancers is linked to enhanced expression of hyaluronan, a pro-angiogenic 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 ERα+ MCF-7 cells, and the highly-aggressive and ERα− 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 ERα. 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 ERα. Only the ERα+ cells showed signs of apoptosis, as determined by cleaved PARP-1, and anoikis as shown by concurrent loss of E-cadherin and β-catenin. Interestingly, 4-MU significantly reduced migration, adhesion and invasion of ERα− 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. •Enhanced hyaluronan synthesis promotes the malignant phenotype of various cancers, including breast cancer•4-MU-mediated suppression of HAS2-synthesized hyaluronan and CD44 is more prevalent in ERα− breast cancer cells•The tumor suppression function of 4-MU promotes CD44-dependent adhesion•4-MU opposes breast cancer progression by regulating matrix-degrading enzymes and inflammatory mediators•The effects evoked by 4-MU are dependent on the ER status of breast cancer