Steroidal hormones and proliferation, differentiation and apoptosis in breast cells.

The impact of estrogens (E) and progestins (P) on the breast is crucial. Recent epidemiological studies raised a great concern concerning breast cancer risk and hormone replacement therapy (HRT). However, the effects of HRT in breast tissue remain unclear. Biological data predominantly show that P are antiproliferative and proapoptotic at least for normal breast cells. These antiproliferative effects of P are well described at the cellular level. Whereas E2 increases the level of the various cyclins involved in the cell cycle progression and decreases the cyclin kinase inhibitors, p21 and p27, progestins act in an opposite manner. In addition, they both modulate the phosphorylated rate of Rb involved into the S phase progression. Various proteins of the apoptotic cascade are also targets for E2 and P. We showed that bcl-2, p53 and caspase 3 are oppositely modulated by E2 and P in normal and breast cancer cell cultures. It is very possible that in vivo the balance between E2/P, the type of P, specific phenotypes could explain increasing risk during HRT, which appears to be mainly a promoter effect on preexisting transformed cells.