Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds.
OBJECTIVE
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.


METHODS
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.
D000362:Agar / Q000737:chemistry; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D002455:Cell Division; D045744:Cell Line, Tumor; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D008525:Medroxyprogesterone / Q000494:pharmacology*; D017258:Medroxyprogesterone Acetate / Q000378:metabolism; D016296:Mutagenesis; D054778:NM23 Nucleoside Diphosphate Kinases; D009362:Neoplasm Metastasis; D009701:Nucleoside-Diphosphate Kinase; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012323:RNA Processing, Post-Transcriptional; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D003280:Contraceptives, Oral, Synthetic; D005938:Glucocorticoids; D054778:NM23 Nucleoside Diphosphate Kinases; D003907:Dexamethasone; D000362:Agar; D017258:Medroxyprogesterone Acetate; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D008525:Medroxyprogesterone