Retinoid carboxylic acids, the natural derivatives and synthetic analogs of vitamin A, are fundamental mediators of many biological processes, including differentiation, proliferation, and morphogenesis. The observations that retinoids have striking activity in the treatment of acute promyelocytic leukemia (APL), advanced skin and cervical cancers and head and neck cancer have generated tremendous enthusiasm for the development of retinoids for cancer treatment. However, retinoid-retinoid-resistant cancer cells and severe side effects have restricted further applications. Understanding of the molecular mechanism of retinoid action against breast cancer cell growth will enable us to enhance retinoid sensitivity an design retinoids with greater therapeutic efficacy. The effects of retinoids are mainly mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The retinoid receptors and a number of orphan receptors belong to the steroid/thyroid hormone receptor family that regulates gene expression by binding to specific DNA sequences in target genes. Research Project Molecular Mechanism of Retinoid Action focuses on mechanistic studies of the retinoid response in breast cancer cells and identification of the most effective synthetic retinoids for treatment of breast cancer. Recently, the Zhang laboratory demonstrated that RARbeta mediates the growth inhibitory effect of trans-retinoic acid (trans-RA) in breast cancer cells and subsequently, that trans-RA sensitivity I lung cancer cells is established by the dynamic equilibrium and heterodimerization of the orphan nuclear receptors COUP-TF and nur77, which regulates RARbeta expression. A pEA3-binding site in the RARbeta promoter was also identified. The proposed mechanistic studies are based on these exciting new results. We will first determine the requirement of estrogen receptor and RARalpha on RARbeta gene expression in breast cancer cells, then investigate the role of COUP-TF and nur77 in regulating trans-RA sensitivity in breast cancer cells and the mechanism leading to lack of COUP-TF expression in trans-RA-resistant breast cancer cells. The collaboration with the Leid laboratory will determine how ligand activation of nur77/RXR heterodimers regulates RARbeta promoter activity and the requirement of pEA3 in RARbeta promoter activity. The evaluation of retinoids from the Dawson laboratory will involve identification of potent agonists and antagonists for specific nuclear receptors, characterization of receptor-selective anti-AP-1 activity, and induction of apoptosis and analysis of their growth inhibitory effects against breast cancer cells. The results from these studies will enhance our understanding of the biological functions of retinoid and orphan receptors and the mechanism of retinoid resistance in breast cancer cells, and will provide a rational basis for identifying more effective selective retinoids with reduced side effects.

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National Cancer Institute (NCI)
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Molecular Medicine Research Institute
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Xia, Zebin; Cao, Xihua; Rico-Bautista, Elizabeth et al. (2013) Relative impact of 3- and 5-hydroxyl groups of cytosporone B on cancer cell viability. Medchemcomm 4:332-339
Dawson, Marcia I; Xia, Zebin (2012) The retinoid X receptors and their ligands. Biochim Biophys Acta 1821:21-56
Dawson, Marcia I; Xia, Zebin; Jiang, Tao et al. (2008) Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and J Med Chem 51:5650-62
Farhana, Lulu; Dawson, Marcia I; Leid, Mark et al. (2007) Adamantyl-substituted retinoid-related molecules bind small heterodimer partner and modulate the Sin3A repressor. Cancer Res 67:318-25
Dawson, Marcia I; Xia, Zebin; Liu, Gang et al. (2007) An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and J Med Chem 50:2622-39
Cavasotto, Claudio N; Liu, Gang; James, Sharon Y et al. (2004) Determinants of retinoid X receptor transcriptional antagonism. J Med Chem 47:4360-72
Dawson, M I (2004) Synthetic retinoids and their nuclear receptors. Curr Med Chem Anticancer Agents 4:199-230
Dawson, Marcia I; Harris, Danni L; Liu, Gang et al. (2004) Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest. J Med Chem 47:3518-36
Farhana, Lulu; Dawson, Marcia I; Huang, Ying et al. (2004) Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities. Oncogene 23:1874-84
Rishi, Arun K; Zhang, Liyue; Boyanapalli, Madanamohan et al. (2003) Identification and characterization of a cell cycle and apoptosis regulatory protein-1 as a novel mediator of apoptosis signaling by retinoid CD437. J Biol Chem 278:33422-35

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