Hyaluronic acid induction on breast cancer stem cells unfolds subtype specific variations in stemness and epithelial-to-mesenchymal transition.

The reoccurrence of breast cancer is a major concern due to presence of cancer stem cells (CSCs). Considering the key role of hyaluronic acid (HA) in modulating the inflammation and cellular migration in cancer, the response of high molecular weight (HMW) and low molecular weight (LMW) HA towards various subtypes of breast cancer and breast cancer stem cells remain elusive. The aim of this study is to determine the effect of exogenous HMW-HA and LMW-HA on stemness of CSCs and epithelial-to-mesenchymal transition which may help in designing HA based therapeutic strategies. LMW-HA induces EMT in MCF-7 more prominently as compared to MDA-MB-231. However, HMW-HA did not show significant changes in the expression of EMT genes. Surprisingly, both HMW-HA and LMW-HA have shown to decrease the expression of EpCAM in MCF-7 cells and decrease the expression of CD44 in MDAMB-231 cells. HA has maintained the native stem cells phenotype of bCSCs isolated from MCF-7 only. The bCSCs isolated form MDAMB-231 showed a decrease in CD44. Luminal subtype has shown to follow Wnt/β-catenin whereas in the basal subtype localization of CD44 from surface to cytosol was observed in response to HA. Our study has demonstrated that bCSCs in luminal and basal cells follow differential intracellular signaling mechanisms in response to HA. This study could significantly influence the therapeutics involving HA in breast cancer.