Retinoids and breast cancer: new clues to increase their activity and selectivity

The results presented by Bosch and colleagues [1] in the previous issue of Breast Cancer Research are a major step towards the identification of the critical determinants controlling the responses of breast tumor cells to alltrans-retinoic acid (ATRA), the prototype of retinoids, a promising class of anti-cancer agents. The authors demonstrate that the two retinoid nuclear receptors RARα and RARγ play opposite roles in controlling the growth of breast cancer cells [1]. Retinoid-dependent activation of RARα arrests the growth, while activation of the other receptor favors the proliferation of the neoplastic cell. Suppression of RARγ activity enhances the antiproliferative effects of ATRA in cultures of breast cancer cell lines and in an appropriate animal model of the tumor. Finally, the RARα agonist AM580 [2] is more effective than the pan-RAR ligand, ATRA [3,4], in controlling the growth of breast cancer cells both in vitro and in vivo. This is consistent with the intrinsic ability of ATRA to activate RARα and RARγ simultaneously.ATRA is the only example of a clinically useful cyto-differentiating agent in oncology [3,4], having changed the natural history of acute promyelocytic leukemia, a rare form of acute myelogenous leukemia [5]. This along with promising results obtained in preclinical models has spurred interest in the use of ATRA and natural (9-cis and 13-cis retinoic acid) or synthetic derivatives (retinoids) also for the management of solid tumors, with particular reference to breast cancer. However, the clinical experience accrued with ATRA and derivatives in breast cancer has not kept up with expectations [6]. Indeed, so far, promising results have been obtained only with the atypical synthetic retinoid fenretinide, which is effective in the secondary prevention of pre-menopausal breast tumors [7].One of the reasons for the poor clinical outcome of ATRA in breast cancer may be linked to the heterogeneity of this tumor, which is a collection of distinct