Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity
2009 (English)In: Experimental Cell Research, ISSN 0014-4827, Vol. 315, no 1, 1-9 p.Article in journal (Refereed) Published
Transforming growth factor-beta 1 (TGF-beta 1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta 1 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-beta 1. Intracellular TGF-beta 1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta 1. Inhibition of MMP activity restored TGF-beta 1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta 1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta 1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta 1 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-beta 1 levels.
Place, publisher, year, edition, pages
2009. Vol. 315, no 1, 1-9 p.
Sex steroids, Breast cancer, TGF-beta l, MMP, Angiogenesis, Nude mice
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-16417DOI: 10.1016/j.yexcr.2008.10.015OAI: oai:DiVA.org:liu-16417DiVA: diva2:139580
Ulrika Nilsson, Jill A Jönsson and Charlotta Dabrosin, Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity, 2009, EXPERIMENTAL CELL RESEARCH, (315), 1, 1-9.
Copyright: Elsevier Science B.V., Amsterdam