We previously reported reciprocal regulation of extracellular matrix degrading enzymes and their endogenous inhibitors by NFkappaB. As such, dominant negative inhibition of NFkappaB in a murine lung alveolar carcinoma cell, Line 1, afforded a decrease in malignant proclivity [Cancer Res. 60(23) (2000) 6557-6562]. Contrasting the gene expression profile of malignant Line 1 tumor cells (WT-Line 1) and their non-malignant counterparts transduced with a dominant negative inhibitor of NFkappaB (mIkappaB-Line 1), we observed upregulated retinoic acid receptors (RARs) and the cAMP response element modulator (CREM), in mIkappaB-Line 1 tumor cells, and utilized heterologous promoter-reporter constructs to confirm enhanced responsiveness. We translate these findings by inducing retinoid and cAMP transcriptional programs in WT-Line 1 tumor cells with pharmacologic doses of all-trans retinoic acid (at-RA) and pentoxyfilline (PTX), respectively, and demonstrate suppression of NFkappaB activity, tumor cell derived matrix metalloprotease 9 activity, tumor cell invasiveness in vitro and spontaneous metastasis in vivo. Our results are consistent with the putative role of retinoids and cAMP in the malignant reversion of tumor cells and illustrative of the binary nature of transcriptional programs that modulate malignant progression.