Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases.
Until recently, relaxin (RLX) has been known predominantly for its effects on the reproductive system, where it induces remodelling of the extracellular matrix and up-regulation of matrix metalloproteases (MMPs). In solid cancers, tissue remodelling and MMP activation are essential for invasion and metastasis. We therefore investigated the effect of RLX on invasiveness and MMP expression of human breast cancer cell lines. Upon incubation with porcine RLX, the invasiveness of SK-BR3 cells was significantly increased. Similar effects could be achieved in MCF-7 cells, especially when RLX was combined with epidermal growth factor. Enhanced invasiveness was accompanied by up-regulation of MMP production and could be almost completely blocked by the MMP inhibitor FN 439. Zymography revealed increased secretion of MMP-2, -7 and -9, associated with up-regulated mRNA concentrations of MMP-2, -9, -13 and -14. mRNA expression levels of MMP-1, -3, -7, -8, -10, -11, -12 and of tissue inhibitors of metalloproteases-1, -2, -3 and -4 were either very low or not detectably influenced by RLX. Taken together, RLX enhances in-vitro invasiveness of breast cancer cell lines by induction of MMP expression. It remains to be clarified whether RLX might play a similar role in vivo and promote tumour progression.
Binder
C
C
Department of Hematology/Oncology, Georg-August-University, Robert-Koch Str. 40, D-37075 Göttingen, Germany. cbinder@med.uni-goettingen.de
Hagemann
Th
T
Husen
B
B
Schulz
M
M
Einspanier
A
A
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009842:Oligopeptides / Q000494:pharmacology; D012065:Relaxin / Q000378:metabolism* / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000097792:Tissue Inhibitor of Metalloproteinase-4
D017364:Collagenases; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D006877:Hydroxamic Acids; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D020783:Matrix Metalloproteinase 7; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D012065:Relaxin; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; C507079:MMP13 protein, human