6th ESACP Congress, Heidelberg, April 7-11, 1999

A093
4-OH TAMOXIFEN INDUCES SUPRAMOLECULAR REMODELLING OF CHROMATIN IN NORMAL HUMAN BREAST EPITHELIAL CELLS IN VIVO
Linares-Cruz G 1, Chassoux D 2, Simony J 3, Fournier S 5, Rouanet Ph 4, Calvo F 1

1) Laboratoire de Pharmacologie Expérimentale, Institut de Génétique Moléculaire Saint Louis, Paris, 2) INRA 806, IBPC, Paris, 3) Laboratoire de Pathologie, CRLCC Val d'Aurelle, Montpellier, 4) Department de Chirurgie, CRLCC Val d'Aurelle, Montpellier. 5) Laboratoires Besins ISCOVESCO, Paris.

The remarkable tissue-specific behaviour of Tamoxifen was recently demonstrated in the BCPT Trial. In the group of women at high risk for breast cancer who received Tamoxifen treatment, there was an increase of endometrial cancer but a reduced occurrence of certain bone fractures and a dramatic 45% reduction in breast cancer incidence. Thus, considering the systemic effects, there is a great need to improve existing therapies for the prevention of breast cancer. Tamoxifen belongs to a class of molecules known as selective estrogen receptor modulators (SERMs) The selective antagonist 4-OH-Tamoxifen (4-OHT) is the active metabolite of Tamoxifen. The rational design for the optimisation of SERMs like 4-OHT is to concentrate their activity in the breast and to avoid as much as possible systemic circulation. It was demonstrated that 4-OHT penetrates through the skin. Thus a percutaneous selective concentration in breast tissues could be envisaged. A major contribution to the understanding of the 4-OHT ligand chemistries upon Estrogen Receptor alpha (ERa) ligand binding domain (LBD) was reported recently. Hitherto the modulation of biomarkers after Tamoxifen therapy has focused on proliferation and apoptosis related molecules. Here in we demonstrate in patients treated with Tamoxifen per Os or with 4-OHT percutaneously a supramolecular remodelling of the chromatin in breast epithelial cells by DNase I genome exposure analysis in paraffin embedded tissues. We suggest that chromatin remodelling could be used as a monitoring parameter in cancer prevention in 4-OHT percutaneous therapy.