Epidemiological evidence suggests that due to its high isoflavone (genistein and daidzein) content a diet rich in soy could protect against breast cancer, particularly tumours expressing oestrogen receptor alpha (ERα+). Isoflavones are weakly oestrogenic, and have other wide ranging cellular activities. Contradictory in vitro evidence means that isoflavones’ mechanism(s) of action remain to be elucidated. ERα+ MCF7 and ERα-/ERβ+ MDA-MB-231 cell proliferation and apoptosis were quantified at a range of achievable serum concentrations of genistein or daidzein (0.01nM to 31.6μM) with or without pre-/post-menopausal 17β-oestradiol (E2) levels (1nM and 1pM). Additionally, cell volume regulation and macroscopic K+ current modulation by isoflavones and E2 in MCF7 cells were investigated. In MCF7 cells isoflavones (≥1μM) induce apoptosis, even in the presence of E2, but this did not reverse the synergistic effect of postmenopausal E2 and isoflavones on proliferation. Isoflavones slightly reduced MDA-MB-231 proliferation at all concentrations, dropping dramatically at 31.6μM. This response was partially maintained in the presence of postmenopausal E2. Isoflavones also induced markers of apoptosis. Treating MCF7 with 1nM E2 or 1μM genistein resulted in cell swelling, and a significant increase in whole cell current (E2 only), indicating a proliferative response. Conversely, treatment with 31.6μM genistein resulted in shrinkage, and inhibition of outward K+ current (not statistically significant). Daidzein treatment inhibited current to a lesser extent. Co-treatment with K+ channel blockers indicated the hEAG channel as a potential molecular target of genistein in MCF7. These results suggest that in ERα+ breast cancers, isoflavones may act by inducing apoptosis, shrinkage, and inhibition of hEAG current. There was no evidence suggesting that isoflavones reduce E2-promoted ERα+ cancer cell proliferation. Importantly, the inhibition of K+ channel activity by isoflavones represents a novel target for anti-cancer therapies. However, even low levels of isoflavones may be beneficial chemotherapeutic agents against ERα-/ERβ+ breast cancer, indicating an urgent requirement for further characterization of the effects of isoflavones in these breast cancers.sub_dnbsunpub1282_ethesesunpu
