title: Effects of SDF-1-CXCR4 signaling on microRNA expression and tumorigenesis in estrogen receptor-alpha (ER-α)-positive breast cancer cells.
abstract: The majority of breast cancer cases ultimately become unresponsive to endocrine therapies, and this progression of breast cancer from hormone-responsive to hormone-independent represents an area in need of further research. Additionally, hormone-independent carcinomas are characterized as being more aggressive and metastatic, key features of more advanced disease. Having previously shown the ability of the stromal-cell derived factor-1 (SDF-1)-CXCR4 signaling axis to promote primary tumorigenesis and hormone independence by overexpressing CXCR4 in MCF-7 cells, in this study we further examined the role of SDF-1/CXCR4 in the endogenously CXCR4-positive, estrogen receptor α (ER-α)-positive breast carcinoma cell line, MDA-MB-361. In addition to regulating estrogen-induced and hormone-independent tumor growth, CXCR4 signaling stimulated the epithelial-to-mesenchymal transition, evidenced by decreased CDH1 expression following SDF-1 treatment. Furthermore, inhibition of CXCR4 with the small molecule inhibitor AMD3100 induced CDH1 gene expression and inhibited CDH2 gene expression in MDA-MB-361 cells. Further, exogenous SDF-1 treatment induced ER-α-phosphorylation in both MDA-MB-361 and MCF-7-CXCR4 cells, demonstrating ligand-independent activation of ER-α through CXCR4 crosstalk. qPCR microRNA array analyses of the MDA-MB-361 and MCF-7-CXCR4 cell lines revealed changes in microRNA expression profiles induced by SDF-1, consistent with a more advanced disease phenotype and further supporting our hypothesis that the SDF-1/CXCR4 signaling axis drives ER-α-positive breast cancer cells to a hormone independent and more aggressive phenotype. In this first demonstration of SDF-1-CXCR4-induced microRNAs in breast cancer, we suggest that this signaling axis may promote tumorigenesis via microRNA regulation. These findings represent future potential therapeutic targets for the treatment of hormone-independent and endocrine-resistant breast cancer.
authors: Department of Medicine, Tulane University Health Sciences Center, 1430 Tulane Ave, New Orleans, LA 70112, USA. Lvanhoy@tulane.edu
authors: Lyndsay V
authors: LV
authors: Rhodes
authors: Melyssa R
authors: MR
authors: Bratton
authors: Yun
authors: Y
authors: Zhu
authors: Syreeta L
authors: SL
authors: Tilghman
authors: Shannon E
authors: SE
authors: Muir
authors: Virgilio A
authors: VA
authors: Salvo
authors: Chandra R
authors: CR
authors: Tate
authors: Steven
authors: S
authors: Elliott
authors: Kenneth P
authors: KP
authors: Nephew
authors: Bridgette M
authors: BM
authors: Collins-Burow
authors: Matthew E
authors: ME
authors: Burow
mesh_terms: D000818:Animals; D001596:Benzylamines; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D016133:Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D047628:Estrogen Receptor alpha; D006571:Heterocyclic Compounds; D035683:MicroRNAs; D019718:Receptors, CXCR4; C088327:plerixafor