Abstract CN05-03: Cooperation between a rexinoid and EGFR-TKI for lung cancer prevention via Cyclin D1 destabilization

We previously reported that both nuclear retinoic acid receptor (RAR, retinoid) and retinoid X receptor (RXR, rexinoid) agonists can trigger proteasomal degradation of cyclins. This confers check point arrest and repair of carcinogenic DNA damage in bronchial epithelial cells. Mechanisms responsible for this induced degradation were discovered. These included ubiquitin-dependent as well as ISG15-dependent programs that independently destabilized expression of cyclin D1 and other G1 cyclin proteins. The critical receptor that confers this cyclin destabilization was RARβ. Yet, silencing of RARβ; and specifically of the previously unrecognized isoform that we cloned and designated as RARβ1 likely accounts for clinical resistance to classical retinoids (like 13-cis-retinoic acid and all-trans-retinoic acid) in lung carcinogenesis. We sought to learn whether RXR/RAR heterodimer complex activation with a rexinoid was able to trigger cyclin destabilization. This was found to be the case in in vitro studies. This finding implied that the same pathway would be engaged in the in vivo setting. To establish if this occurs, we engineered transgenic mice independently with human surfactant C-driven wild-type cyclin E or a proteasome-degradation resistant cyclin E species. This mouse model was developed because human pre-malignant and malignant lung lesions frequently deregulate cyclin expression. Intriguingly, these mice recapitulated many features of lung carcinogenesis fou...
Source: Cancer Prevention Research - Category: Cancer & Oncology Authors: Tags: Combinatorial Approaches to Chemoprevention: Oral Presentations - Invited Abstracts Source Type: research