Retinoids and Retinoid Metabolism in Breast Cancer

摘要

Retinoids play diverse roles in human physiology. Retinoid actions are mediated via retinoid receptors (RARs and RXRs). Little is known about the biosynthetic pathway of 9-cis-retinoic acid, the physiological ligand for RXRs. Thus, we studied cis-retinol dehydrogenase (cRDH), an enzyme that oxidizes cis- retinols, a first step needed for 9-cis-retinoic acid synthesis. LRDHSN/Hep O2 cells were developed to study the characteristics of cRDH and its role in 9-cis- retinoic acid synthesis. We observed that cRDH oxidizes 9-cis-retinol and follows Michaelis-Menten kinetics. Nonetheless, cRDH over-expression did not result in increased synthesis of 9-cis-retinoic acid, which likely arises from the inhibition of 9-cis-retinal oxidation by high concentrations of 9-cis- retinol in vitro. We also studied the role of cRDH in 9-cis-retinol metabolism and in cell proliferation of MCF7 cells, a human breast cancer line. We demonstrated that both cRDH and 9-cis-retinol treatment were required to bring about a growth inhibitory effect on MCF7 cells. This growth inhibition was not mediated by 9-cis-retinoic acid but by other 9-cis-retinol metabolites like 9- cis-retinal and/or an unknown metabolite. Our studies suggest that a two pronged approach of targeted gene therapy with cRDH in combination with a low dose of 9- cis-retinol treatment may be a useful breast cancer treatment.