Tibolone and its main derivatives were studied in an original model of cult
ures of normal human epithelial breast (HBE) cells on proliferation, differ
entation and apoptosis, the three mechanisms responsible for breast homeost
asis. Tibolone and its Delta4 isomer were antiproliferative, both in the ab
sence and presence of oestradiol (E2). The oestrogenic 3 alpha and 3 beta h
ydroxy derivatives did not display any mitogenic activities in HBE cells. M
oreover, at 1 muM, they were antiproliferative. Tibolone and its Delta isom
er increased the 17 beta hydroxysteroid dehydrogenase activity similarly to
that observed with progestins [1]. Apoptosis was increased in HBE cells to
a similar range as with the pure pregnane progestin, Org2058. We also stud
ied the extent of apoptosis in hormone-dependent breast cancer cell lines.
Tibolone and its Delta4 isomer also increased apoptosis, especially in ZR75
-1 cells containing progesterone and androgen receptors [2]. We could demon
strate that these pro-apoptotic actions of tibolone and its Delta4 isomer w
ere mediated at least partially through the bcl-2-family of proteins. Moreo
ver, the antiproliferative and pro-apoptotic activities of tibolone, as wel
l as Org2058, were mediated by increasing catalase activities in breast can
cer cells. Thus, in breast cells, tibolone slows down the proliferation rat
e, increases differentiation and apoptosis. These actions seem to be optima
l on breast tissue. (C) 2000 Elsevier Science Ltd. All rights reserved.