Effects of Hyaluronan on Breast Cancer Aggressiveness

The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.