Proapoptotic eects of antiestrogens, progestins and androgen in breast cancer cells

The promoting action of E2 in breast cancer cells has been, until now, mainly linked to its action on proli®eration. Because of the importance of an increase in apoptosis in breast cancer prevention, we have studied the possible e€ects of various antiestrogens, progestins and an androgen on its occurrence in three hormone-dependent breast cancer cell lines. The antiestrogens were, a triphenylethylene derivative, 4 hydroxytamoxifen(4OHTAM) and two steroidal antiestrogens, ICI182780 and RU58668. The progestins were Org2058, a pregnane derivative, tibolone (OrgOD14), a normethyltestosterone derivative and OrgOM38 (the D4 isomer of OrgOD14) and the androgen dihydrotestosterone (DHT). Apoptosis was studied in MCF-7, ZR751 and T47-D cells using morphological approaches and ̄ow cytometry. The antiestrogens, the progestins and DHT were proapoptotic but to di€erent potencies according to the cell line studied. Indeed, the `pure' steroidal antiestrogens were more ecient than 4OHTam in increasing apoptosis. We have also studied the level of expression of some of the proteins involved in the regulation of apoptosis. Bcl-2 and bcxL, two antiapoptotic members of the bcl-2 family proteins, were inhibited by the progestins and the antiestrogens. In contrast, the proapoptotic proteins, bax and bak seemed to be constitutively expressed. Thus, since the ratio of proapoptotic and antiapoptotic proteins determines apoptosis or cell survival, the hormone e€ects are operating by modulating the antiapoptotic regulators of the balance. These data demonstrate that antiestrogens, progestins, and androgens can promote apoptosis in breast cancer cells, an e€ect which could be of importance in the therapeutic prevention of breast cancer. # 1999 Elsevier Science Ltd. All rights reserved.