Abstract
Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) that plays a pivotal role in breast cancer. While HA is the only GAG not normally substituted with sulfate groups, sulfated hyaluronan (sHA) has previously been used in studies with promising antitumor results. The aim of the present study was to evaluate the effects sHA fragments have on breast cancer cells with different estrogen receptor (ER) status. To this end, ERα-positive MCF-7, and ERβ-positive MDA-MB-231 cells were treated with non-sulfated HA or sHA fragments of 50 kDa. The functional properties of the breast cancer cells and the expression of key matrix effectors were investigated. According to the results, sHA attenuates cell proliferation, migration, and invasion, while increasing adhesion on collagen type I. Furthermore, sHA modulates the expression of epithelial-to-mesenchymal transition (EMT) markers, such as e-cadherin and snail2/slug. Additionally, sHA downregulates matrix remodeling enzymes such as the matrix metalloproteinases MT1-MMP, MMP2, and MMP9. Notably, sHA exhibits a stronger effect on the breast cancer cell properties compared to the non-sulfated counterpart, dependent also on the type of cancer cell type. Consequently, a deeper understanding of the mechanism by which sHA facilitate these processes could contribute to the development of novel therapeutic strategies.
Highlights
Breast cancer is characterized by high heterogeneity and constitutes one of the most commonly reported types of cancer globally [1]
In order to evaluate the effects of sulfated hyaluronan (sHA) on the ERα-positive MCF-7 and the ERαnegative/ERβ-positive MDA-MB-231 cell lines, the cells were treated with non-sulfated
The obtained results indicate a slight decrease in the proliferation capability of the MCF-7 cells for both HA fragments tested (Figure 1A)
Summary
Breast cancer is characterized by high heterogeneity and constitutes one of the most commonly reported types of cancer globally [1]. Throughout disease development, the expression patterns of the estrogen receptors (ERs) are crucial for regulating breast cancer cell properties, morphology, as well the expression of several effectors associated with aggressiveness of the malignancy [2,3,4]. Depending on the ER status, breast cancer cells are categorized into ERα-positive, with epithelial characteristics and low metastatic potential, and ERα-negative, which exhibit higher metastatic potential and are associated with more aggressive phenotypes [5]. Cellular phenotypes can be altered due to epithelial-to-mesenchymal transition (EMT), which leads to loss of cell polarity and cell-to-cell junctions, facilitating cellular migration and metastasis [6,7]. Overexpression of matrix enzymes, such as matrix metalloproteinases (MMPs) accounts for the extensive reorganization of the extracellular matrix (ECM), further contributing to cell migration and invasion [11]
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