The Molecular Basis of Retinoids’ Use in Breast Cancer Chemoprevention

Abstract

Whereas encouraging, interpretations of available data regarding retinoids’ effectiveness in breast cancer chemoprevention, e.g. [5,7] fail to address pivotal molecular aspects concerning their employment in clinical trials. The rationale for using retinoids in chemoprevention is primarily based on their ability to coordinately regulate differentiation, proliferation and apoptosis. The discovery of their receptors and cognate upand downstream signaling cascades has emerged a great progress in the understanding of their molecular actions. Moreover, it has been recently suggested that the cross-talk between retinoid receptors and other signal transduction pathways might represent a “switch on/off” function model that is deregulated from the very early steps of carcinogenesis [3]. Retinoids, through retinoid acid receptors (RARs), mainly modulate proliferation/differentiation axes. In addition to their positive effects, particularly those correlated with differentiation, RARs also function as negative-acting transcription factors. One of the wellknown transcriptional repressive effects of RARs is their inhibition of activator protein-1 (AP-1) activity. With regard to breast carcinogenesis, there is evidence that retinoids suppress estradiol-mediated proliferation and transcriptional activity and can antagonize the proliferative effects of AP-1. Crucial genetic/epigenetic events early in carcinogenesis, such as over-expression of epidermal growth factor receptor (EGFR) family proteins and gradual down-regulation of RARβ ex-