S100A8/A9 mediate the reprograming of normal mammary epithelial cells induced by dynamic cell-cell interactions with adjacent breast cancer cells

Abstract

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

Characterization of Gene Expression Signatures for the Identification of Cellular Heterogeneity in the Developing Mammary Gland

“…These results suggest an accumulation of partially differentiated luminal secretory cells in mammary tissue from a never pregnant, post-pubescent female mouse. We found that mEC4 cells expressed higher levels of Lactalbumin Alpha (Lalba) and S100 Calcium Binding Protein A8 (S100a8) mRNAs [8,51], while those from mEC5 expressed high levels of Aldehyde Dehydrogenase 1 Family Member A3 (Aldh1a3) and Transferrin (Trf) mRNAs, all previously associated with luminal progenitor cells [27] (Fig. 2B and Supplementary Fig.…”

Breast cancer heterogeneity and its implication in personalized precision therapy

“…Breast cancer cells can transform normal breast epithelial cells to exhibit cancerous properties, including enhanced proliferation and migration, EMT-related features, and loss of apicalbasal polarity [168]. S100A8/A9 can mediate dynamic interaction between normal breast epithelial cells and adjacent breast cancer cells to induce reprogramming [169]. Coculture with breast cancer cells or induction of overexpression of S100A8/A9 revealed that normal epithelial cells exhibit features of EMT, and the capacity of cell proliferation, migration, colony formation, and threedimensional sphere formation is increased [169].…”

Cancer‐associated fibroblasts induce an aggressive phenotypic shift in non‐malignant breast epithelial cells via interleukin‐8 and S100A8

“…It was reported that S100A8 promotes activation of mitogen‐activated protein kinase (MAPK) and NF‐κB signaling pathways in colon cancer cells (Ichikawa et al, 2011). Phosphorylated forms of mTOR and Akt were increased in S100A8‐overexpressing MCF10A cells (Jo et al, 2018). Our study suggests that CAFs upregulate S100A8 in breast epithelial cells, inducing an invasive phenotype, possibly via mTOR and/or MAPK signaling pathways.…”