Impact of syndecan-1 (CD138) on the lateral transmission of aggressive breast cancer cell behavior

Introduction

Breast cancer (BrC) is a complex disease exhibiting extensive inter- and intra-tumor heterogeneity mainly linked to the status of hormonal receptors in both pre- and post-menopausal patients [1,2]. The mammary stroma is important for modulating epithelial breast cell response to sex steroid hormones [3] and the the communication that exist between the tumor cells and their microenvironment, decisively influences tumoral behavior [4]. Interestingly, among postmenopausal women with BrC, the expression of matrix-cell-surface derived proteoglycans such as Syndecan-1 (Sdc-1, CD138), changes from the epithelium to the stroma and correlates with high expression of androgen receptor [3,5]. On the other hand, Sdc-1 is also an important coreceptor for multiple signaling pathways and have been shown to contribute to tumor progression due to their impact on motility, epithelial-to-mesenchymal transition (EMT), and cancer stem cell properties (CSCs) [6,7]. Previously, we reported the capacity of triple-negative cell lines to induce a CSC-like phenotype and invasive properties on luminal cells (lateral transmission of aggressiveness), a mechanism mediated by pro-inflammatory cytokines. Interestingly, the induced invasive/CSC-like cells do not alter their luminal phenotype but turn on expression of androgen receptor [8,9]. We hypothesize that the blocking of Sdc-1 in triple-negative BrC cells reduces the potential to induce the lateral transmission of aggressive traits to non-aggressive Luminal cancer cells as a mechanism to drive breast cancer progression in postmenopausal women.

Methods

Non-aggressive BrC cells were treated with the conditioned media (CM) of knock-down (KD) Sdc-1 aggressive BrC cells or controls and performed an analysis of epithelial-mesenchymal transition, cancer stem cell (CSC), and inflammation markers by qRT-PCR. Migration capacity was analyzed by scratch assay, cell cycle progression was assessed by flow cytometry, and the formation of tumorspheres was analyzed using ultralow attachment plate. Finally, migrations assays were performed on monocytes using the CM as chemoattractant factor.

Results

We found that Sdc-1 is highly expressed by the aggressive cell lines MDA-MB-231 (triple-negative) and SUM-149 (inflammatory). Reduced Sdc-1 expression attenuated the expression of inflammatory-related genes including IL-6, IL-8 and MMP-2. In concordance, the secretion of IL-6, IL-8, CXCL1, CXCL2, angiogenin and VEGF were diminished in both cell lines. Culture of non-aggressive luminal BrC cell line MCF-7 with the CM of MDA-MB-231- and SUM-149-Sdc-1-KD cells or controls, revealed the aggressive cell lines induce: the expression of vimentin, SNAIL-1, CD44, and SOX-2, migration capacity, and altered cell cycle progression and tumorsphere formation on Luminal MCF-7 cells. While all those induced new characteristics were diminished in the cells treated with the CM of Sdc-1-KD cells. Finally, we observed that Sdc-1 is important for the migration of monocytes.

Discussion and Conclusion

Understanding the communication between different populations of cells of BrC and how Sdc-1 contributes to the appearance of new populations with aggressive characteristics, could be important to understand the existence of BrC heterogeneity that could contribute to resistance to treatment and relapse in post-menopausal patients