title: Stearoyl-CoA desaturase 1 and paracrine diffusible signals have a major role in the promotion of breast cancer cell migration induced by cancer-associated fibroblasts.
abstract: BACKGROUND
  Despite the recognised contribution of the stroma to breast cancer development and progression, the effective 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-to-mesenchymal transition and increases in cell membrane fluidity and migration in 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.
  
  
  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. To assess the role of SREBP1 in the regulation of SCD1 expression, the desaturase levels were also determined in tumor cells treated with an SREBP1 inhibitor. Migration was evaluated by wound-healing assay in SCD1-inhibited (by small-interfering RNA (siRNA) or pharmacologically) cancer cells and the effect of CAF-conditioned medium was also assessed. To define the role of stroma-derived signals in cancer cell migration speed, cell-tracking analysis was performed in the presence of neutralising antibodies to hepatocyte growth factor, transforming growth factor-β or basic fibroblast growth factor.
  
  
  RESULTS
  A two to three fold increase in SCD1 mRNA and protein expression has been induced, particularly by CAFs, in the two cancer cell lines that appear to be dependent on SREBP1 activity in MCF-7 but not in MDA-MB-231 cells. Both siRNA-mediated and pharmacological inhibition of SCD1 impaired tumor cells migration, also when promoted by CAF-released soluble factors. Fibroblast-triggered increase in cancer cell migration speed was markedly reduced or abolished by neutralising 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.
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Angelucci
authors.affiliation: Institute of Physics, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Maulucci
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Colabianchi
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Iacopino
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Alessio
authors.affiliation: Institute of Physics, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Maiorana
authors.affiliation: Institute of Physics, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Palmieri
authors.affiliation: Institute of Physics, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Papi
authors.affiliation: Institute of Physics, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Spirito
authors.affiliation: Department of Surgery, Breast Unit, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Leone
authors.affiliation: Department of Surgery, Breast Unit, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine 'A. Gemelli', Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sica
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D018920:Coculture Techniques / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D019899:Paracrine Communication / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase