During normal development and embryogenesis, helix-loop-helix Id proteins regulate the differentiation programs of many tissues. Moreover, recent studies have shown that dysregulated Id expression contributes to cancer progression and metastasis. Specifically, we found high levels of one of the Id family members, Id-1, in breast, prostate, brain and head and neck tumor cells which were highly aggressive, and low levels of Id-1 in non-invasive tumor cells. Ectopic expression of Id-1 in non-aggressive human cancer cells rendered them highly proliferative and invasive, and induced high levels of matrix metalloproteinase (MMP) expression. Conversely, human metastatic cancer cells became significantly less proliferative and invasive in culture when Id-1 protein expression was decreased by antisense RNA or shRNA directed against the Id-1 gene. Next, we asked whether Id-1 could be exploited as a therapeutic target to treat metastatic cancers. Using tumor-bearing animals and systemic gene targeting technique, we showed that reduction of Id-1 levels, and consequently MMP expression, could significantly decrease the metastatic spread of cancer cells. Further, several molecular pathways underlying Id-1 effects on epithelial to mesenchymal transition (EMT) and neoangiogenesis were also identified in certain types of cancer. These results suggested that Id-1 gene and/or protein could be a promising target for development of therapeutic strategies to reduce cancer metastasis. Since Id-1 expression is scarce in most mature adult tissues, a majority of normal cells would not be affected by systemic therapy targeting this gene. We determined that a cannabinoid compound, CBD, could specifically inhibit the expression of the Id-1 gene and, as a result, cancer cell proliferation and invasion in culture and tumor metastasis in vivo. In tumor-bearing mice, we observed significant anti-metastatic effects after daily treatment with CBD. Id-1 expression in tumor cells from lung foci was significantly down-regulated as well as Ki67, a marker of cell proliferation. Finally, CBD prolonged the survival of tumor-bearing mice even though the treatment was initiated after the establishment of metastases. Overall, our data suggest that Id proteins act as key regulators of tumor metastasis and suggest the use of Id genes as novel therapeutic targets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5308. doi:1538-7445.AM2012-5308