Relaxin enhances in-vitro invasiveness of breast cancer cell lines by up-regulation of matrix metalloproteases

Abstract

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.

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

“…14 -17 Relaxin affects proliferation and differentiation of MCF-7 human carcinoma cells in a concentration-dependent manner 18 and can modify the extracellular matrix by affecting the expres-sion of matrix metalloproteinases (MMPs), which potentially contribute to relaxin's role as a migration-promoting peptide in mammary carcinoma cells of different species, 15 including humans. 19 In the present study, we have for the first time revealed novel roles for RLN2 in human thyroid carcinoma cells. We identified neoplastic thyroid tissues as a source of RLN2 and LGR7, implicating an active RLN2-LGR7 signaling system in human thyroid carcinoma.…”

“…Relaxin has previously been identified as a hormone promoting the motility of human and canine mammary carcinoma cell lines (human, MCF-7 and SK-BR3; canine, CF33.Mt) 15,32 as well as noncarcinogenic bronchial epithelial cells and inflammatory cells infiltrating wounds. 33, 34 Here we demonstrate that both recombinant RLN2 and secreted proRLN2 profoundly accelerated the cellular motility of two human thyroid carcinoma cell lines (FTC-133 and FTC-238) and the corresponding RLN2 transfectants in an autocrine/ paracrine LGR7-dependent manner.…”

“…35 MMPs and their tissue inhibitors of metalloproteinases (TIMPs) have been identified to potentially facilitate relaxin's effects on cellular migration and ECM invasion. 31,36 -38 In human mammary carcinoma cells, relaxin was shown to affect the expression profile of specific MMPs 32 and one report indicated a correlation between increased relaxin serum levels and metastases in human breast cancer patients. 39 We demonstrated a strong correlation between relaxin-mediated induction of specific MMPs and degradation of extracellular matrix (ECM) components resulting in enhanced migration of canine mammary carcinoma cells.…”

H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis

“…Gelatin zymography was performed as described previously. 10 Briefly, samples were loaded into an 8% zymogram gel copolymerized with 0.1% gelatin under nonreducing conditions. Gels were then washed twice with a 2.5% Triton X-100 solution for 30 min, followed by a 30 min wash in incubation buffer (50 mM Tris-HCl buffer pH 8.0, 5 mM CaCl 2 and 1 lM ZnCl 2 ; pH 8.0).…”

“…8 However, the regulation of these enzymes by relaxin have also been suggested as a mechanism for its role in facilitating cancer cell migration and invasion. [9][10][11] Although the biological significance of relaxin in the male remains elusive, the prostate gland appears to be relaxin's main source. 8 In the human, there are 3 relaxin alleles encoding 3 hormones, named H1, H2 and H3.…”