Tamoxifen decreases extracellular TGF-beta1 secreted from breast cancer cells--a post-translational regulation involving matrix metalloproteinase activity.
Transforming growth factor-beta1 (TGF-beta1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta1. Intracellular TGF-beta1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta1. Inhibition of MMP activity restored TGF-beta1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta1 levels.
Nilsson
Ulrika W
UW
Linköping University, Department of Clinical and Experimental Medicine, Division of Oncology, University Hospital, SE-581 85 Linköping, Sweden.
Jönsson
Jill A
JA
Dabrosin
Charlotta
C
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004958:Estradiol / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000201:enzymology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017077:Culture Media, Conditioned; D061965:Matrix Metalloproteinase Inhibitors; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen; D004958:Estradiol; D020780:Matrix Metalloproteinase 9