| Phytoestrogens are a class of estrogen-like compounds available from plants. Epidemiological studies suggest that phytoestrogens have protective actions against breast cancer. We studied the effects of phytoestrogens on growth, cell cycle progression and apoptosis of estrogen receptor (ER)-negative MDA-MB-468 human breast cancer cells. Our results showed that the phytoestrogens genistein and quercetin decreased cell growth, which was associated with a G2/M cell cycle arrest. In addition, genistein and quercetin induced a majority of the cells to undergo apoptosis by 24 h of treatment. An important molecular target of genistein and quercetin in these ER-negative cells appears to be cyclin B1.; Genistein is known to elicit weak estrogenic response in ER-positive breast cancer cells. In order to understand the differences in the mechanism of their estrogenic activity, we studied the structural changes in estradiol-bound and genistein-bound ER. Our results, using sucrose density gradient centrifugation showed that recombinant ERα, ERβ and MCF-7 cellular ER sedimented in a multimeric state (7S), in the presence of estradiol. In contrast, ER-bound to genistein sedimented as a monomer (3.5 - 4S) form, suggesting a possible reason for the low estrogenic activity of genistein.; Breast cancer growth is stimulated by proliferative actions of estradiol, growth factors and polyamines. Our investigation on the efficacy of a combination of ICI182780 (a pure estrogen antagonist) and a bis(ethyl)spermine analog, BE-3-3-3 showed significant growth inhibition and apoptosis on ER-positive breast cancer cells, compared to their use as single agents. The compounds decreased the level of the antiapoptotic proteins, Bcl-2 and Bcl XL, and increased the level of the proapoptotic protein Bax. Activation of caspase 8 and a decrease in estrogen responsive element-mediated transactivation was also observed with BE-3-3-3 and ICI182780 co-treatment. These results suggest that a combination of ICI182780 and BE-3-3-3 may be useful for breast cancer treatment.; We also investigated the chemotherapeutic efficacy of a combination of BE-3-3-3 or BE-4-4-4 and a triplex forming oligonucleotide (TFO). For this purpose, the protooncogene c-myc, overexpressed in about 35% of breast cancers, was used as a target. Our results showed that the polyamine analogs stabilized the sequence-specific triplex DNA formation and decreased the level of c-myc mRNA in breast cancer cells. In addition, TFO in combination with either BE-3-3-3 or BE-4-4-4 inhibited the growth and induced apoptosis of these cells. Thus, TFO complexed with BE-3-3-3 or BE-4-4-4 has promising potential in breast cancer therapy.; In conclusion, our results on phytoestrogens and polyamine analogs illustrate pathways for their action in ER-negative and -positive breast cancer cells. Since these subsets of breast cancer require separate approaches to therapy, knowledge on their growth inhibitory and apoptotic pathways is useful in the design of effective treatment or prevention strategies. |
