Research objectives and content Nuclear receptor ligands (e.g. steroid and thyroid hormone, vitamin D and retinoid agonists and antagonists) are known to modulate cell proliferation, differentiation and apoptosis both in vivo and in vitro. Endocrine therapies in breast and prostate cancer are routinely used in the clinic, and retinoid treatment has largely improved the prognosis of acute promyelocytic leukemia.Moreover a variety of other cancers show promise for treatment with nuclear receptor ligands. Yet, despite the medical and pharmaceutical importance of the nuclear receptor family, and despite rapidly accumulating knowledge about the key players regulating cell cycling and those promoting or inhibiting cell death, next to nothing is known about the regulatory circuits by which nuclear receptors govern the activities of these 'master' genes. Our aim is to decipher these mechanisms by studying nuclear receptor action at multiple functional levels in breast cancer cells (ER+ and ER- cells), a model system in which proliferation,differentiation and apoptosis are regulated by exposure to estrogens, antiestrogens and retinoids. To achieve this goal we will pursue the following studies: a) define the effects of estrogen and retinoids on expression /activity of known key regulators of cell proliferation and cell death, b) identify and characterize, using differential cloning and display technologies, novel factors implicated in these processes c) investigate how estrogens,antiestrogens and retinoic acid alone or in combination affect the expression of these targets, and d) identify synthetic retinoids which can inhibit breast cancer cells proliferation or induce breast cancer cell death. Training content (objective, benefit and expected impact) The completion of this project will provide an important insight into the mechanistic basis of nuclear receptor-mediated cell cycle regulation and apoptosis, increasing our comprehension of both receptor action and the regulatory circuitries governing cell cycle progression and apoptosis, and pave the way towards novel strategies for therapeutics intervention in cancer. Links with industry / industrial relevance (22) The IGBMC has several links established with European Pharmaceutical companies, such as chering AG Berlin, and Roussel-Uclaf, Paris. Dr Gronemeyer is coordinator of an ongoing BIOMED project (BMH4 CT96-0181) to which both companies contribute, and has completed a BIOTECH project (BIO2-CT93 ()473) to which also the applicants'lab (group leader: Dr. Aranda) contributed, thus creating the original contacts resulting in the present application. Due to the intensive links of the IGBMC, in particular the Gronemeyer laboratory, with the pharmacological sector, any results obtained in the course of the proposed study can be optimally exploited.