The reduced incidence of
breast cancer in certain Eastern countries has been attributed to high soy diets although this evidence is simply epidemiological. One of the major constituents of soy is
genistein, but paradoxically this
phytoestrogen binds to oestrogen receptors and stimulates growth at concentrations that would be achieved by a high soy diet, but inhibits growth at high experimental concentrations. To determine the effects of low-dose, long-term
genistein exposure we have cultured MCF-7
breast cancer cells in 10 nM
genistein for 10-12 weeks and investigated whether or not this long-term
genistein treatment (LTGT) altered the expression of oestrogen receptor alpha (
ERalpha) and the activity of the PI3-K/Akt signalling pathway. This is known to be pivotal in the signalling of
mitogens such as
oestradiol (E(2)),
insulin-like growth factor-1 (IGF-1) and
epidermal growth factor (
EGF). LTGT significantly reduced the growth promoting effects of E(2) and increased the dose-dependent growth-inhibitory effect of the PI3-K inhibitor,
LY 294002, compared to untreated control MCF-7 cells. This was associated with a significant decreased
protein expression of total Akt and phosphorylated Akt but not
ERalpha.
Rapamycin, an inhibitor of one of the down-stream targets of Akt,
mammalian target of rapamycin (mTOR), also dose-dependently inhibited growth but the response to this
drug was similar in LTGT and control MCF-7 cells. The
protein expression of liver receptor homologue-1 (LRH1), an
orphan nuclear receptor implicated in tumourigenesis was not affected by LTGT. The results show that LTGT results in a down-regulation of the PI3-K/Akt signalling pathway and may be a mechanism through which
genistein could offer protection against
breast cancer.