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¹ Departments of Medicine-Hematology-Oncology and Obstetrics and Gynecology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA² Department of Biology and Molecular Biology, Montclair State University, Montclair, New Jersey 07043, USA³ Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA

(Correspondence should be addressed to P Rameshwar who is now at UMDNJ-New Jersey Medical School, MSB, Rm. E-579, 185 South Orange Avenue, Newark, New Jersey 07103, USA Email: rameshwa{at}umdnj.edu)

The chemokine Stromal-derived factor-1 (SDF-1) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1 is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembrane (TM), GPR and are involved in tumor promotion. SDF-1 regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFB) activation. This study focuses on the mechanism of activation at low SDF-1 in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5' flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1 phosphorylated CREB (P-CREB) via G_i2-PI3K-protein kinase C (PKC)-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP–PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.