Mutual antagonism between retinoic acid receptors and Nuclear Factor Kappa B in the modular control of tumor metastasis.

VB Andela, MD a&b , EM Schwarz PhD, JD Rosenblatt MD c, RJ O'Keefe MD PhD, EJ Puzas PhD, RN Rosier MD PhD

aDepartment of Orthopaedic & bJames P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY USA. cDepartment of Medicine, Hem/Onc Division, University of Miami, Miami Florida USA

Aim: We previously described a pivotal role for the transcription factor NFkB in tumor metastasis based on its reciprocal regulation prometastatic and antimetastatic factors. We subsequently sought the full extent of metastatic gene regulation and the identification of other transacting factors potentially acting in concert with NFkB, Methods: The gene expression profile of metastatic Line 1 tumor cells (murine lung alveolar carcinoma) and their non-metastatic counterparts transduced with a dominant negative inhibitor of NFkB, was done using the Affymetrix microarray platform. Results: Our results support the reciprocal effect of NFkB on metastatic gene expression and identifies retinoic acid receptors (RAR) to be 12 fold induced in the non-metastatic cell line. Increased expression of all RAR subtypes (a,b, g) was confirmed by RT-PCR and we observed a matched increase in RAR mediated signaling events. AGN191309 (an RAR specific antagonist) was observed to mitigate the changes observed in signaling and metastatic gene expression in the non-metastatic cell line. Conclusion: We thus suggest that NFkB and RAR interactions are essential components of the modular control of tumor metastasis. Although all nuclear hormone receptors are known to antagonize NFkB through physical association, non but RARs have been shown to reciprocally regulate prometastatic and antimetastatic gene expression. A specific role for RAR in tumor metastasis is further supported by its exquisite morphogenic properties, an important point of consideration, granted cancer results from a developmental defect, and processes that occur during morphogenesis are redundantly operative in malignant progression.

KEY WORDS: Prometastatic, Antimetastatic, Microarray.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.