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  • Title: Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds.
    Author: Ouatas T, Halverson D, Steeg PS.
    Journal: Clin Cancer Res; 2003 Sep 01; 9(10 Pt 1):3763-72. PubMed ID: 14506169.
    Abstract:
    PURPOSE: Long-term elevation of metastasis suppressor gene expression in micrometastases represents a novel therapeutic strategy for breast and other cancers. We searched for well-tolerated compounds that could elevate Nm23 metastasis suppressor expression in metastatic human breast cancer cell lines. EXPERIMENTAL DESIGN: MDA-MB-435 and MDA-MB-231 human breast carcinoma cells were treated with dexamethasone or medroxyprogesterone acetate (MPA) in cultures containing either charcoal-stripped serum or FCS. Aspects of nm23 expression and function were determined. RESULTS: Previous investigation of the nm23-H1 promoter suggested that glucocorticoids may contribute to the elevation of Nm23-H1 expression. Dexamethasone elevated Nm23-H1 and Nm23-H2 protein levels in two metastatic human breast carcinoma cell lines 2-3-fold over a 4-day time course when cultured in steroid-free culture medium, with high-dose inhibition, via a traditional transcriptional mechanism. Elevation of Nm23-H1 expression was not observed using FCS-containing culture medium, which contains endogenous levels of corticosteroids, limiting the potential in vivo use of dexamethasone. MPA was investigated as a glucocorticoid receptor agonist. MPA elevated breast carcinoma Nm23-H1 protein expression 3-fold over a 10 nM to 1 micro M dose range when cultured in steroid-free or FCS-containing medium, with a shorter time course. Elevation of Nm23-H1 expression in the presence of endogenous corticosteroids found in FCS involved a distinct, glucocorticoid receptor-dependent, posttranscriptional mechanism of action. MPA had no effect on proliferation in vitro but reduced the soft agar colonization of metastatic breast cancer cell lines by approximately 50%. CONCLUSIONS: MPA represents a first generation lead agent for the elevation of Nm23-H1 metastasis suppressor expression and the inhibition of metastatic colonization.
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