Breast cancer-associated fibroblasts promote tumor cell migration: crucial role of Stearoyl CoA Desaturase 1 and paracrine signalings

Background: Despite the recognized contribution of the stroma to breast cancer development and progression, the effective therapeutic targeting of the tumor microenvironment remains a challenge to be addressed. We previously reported that normal fibroblasts (NFs) and, notably, breast cancer-associated fibroblasts (CAFs) induced epithelial-mesenchymal transition and increase in cell membrane fluidity and migration in both well- (MCF-7) and poorly-differentiated (MDA-MB-231) breast cancer cells. This study was designed to better define the role played, especially by CAFs, in promoting breast tumor cell migration. Materials and Methods: Fibroblast/breast cancer cell co-cultures were set up to investigate the influence of NFs and CAFs on gene and protein expression of Stearoyl-CoA desaturase 1 (SCD1), the main enzyme regulating membrane fluidity, as well as on the protein level and activity of its transcription factor, the sterol regulatory element-binding protein 1 (SREBP1), in MCF-7 and MDA-MB-231 cells. Migration was evaluated by wound healing assay in SCD1-inhibited (by small interfering RNA, siRNA, or pharmacologically) tumor cells. To assess the role of stromal-derived signals in cancer cell migration speed, cell tracking analysis was performed in the presence of neutralizing antibodies to hepatocyte growth factor, transforming growth factor-β or basic fibroblast growth factor. Results: A 2-3 fold increase in SCD1 mRNA and protein expression as well as an induction of SREBP1 DNA binding activity has been induced, particularly by CAFs, in the two cancer cell lines. Both siRNA-mediated and pharmacological inhibition of SCD1 impaired tumor cells migration. Fibroblast-triggered increase in cancer cell migration speed was markedly reduced or abolished by neutralizing the above growth factors. Conclusions: These results provide further insights in understanding the role of CAFs in promoting tumor cell migration, which may help to design new stroma-based therapeutic strategies. Supported by the Susan G. Komen Italian Affiliate (Rome, Italy).