Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells

Simple Summary: Breast cancer stem cells (BCSCs) are a small sub-population of cells within tumors with high metastatic potential. We identified biglycan (BGN) as a prospective molecular target in BCSCs that regulates the aggressive phenotypes of these cells. These findings establish a foundation for the development of therapeutics against BGN to eliminate BCSCs and prevent metastatic breast cancer.It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH(+) and CD29(hi) CD61(+) from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NF kappa B transcription factor, p65, and phospho-I kappa B levels upon BGN ablation, indicating regulation of NF kappa B pathway by BGN. To further support our data, we also characterized CD24(-)/CD44(+) BCSCs from human luminal MCF-7 breast cancer cells. These CD24(-)/CD44(+) BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NF kappa B pathway after knockdown of BGN. Finally, loss of BGN in ALDH(+) and CD29(hi) CD61(+) BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer.

Automated summary

Breast cancer stem cells (BCSCs) are a small population of tumor cells with high metastatic potential. The molecule biglycan (BGN) has been identified as a potential molecular target in BCSCs that regulates their aggressive characteristics. Removing BGN reduces BCSC proportions and tumorsphere formation, as well as decreases BCSC-associated migration, invasion, and metabolism. These findings suggest that targeting BGN could be an important therapeutic strategy for treating metastatic breast cancer.