Estrogens, by binding to and activating the estrogen receptor (ERa), are important in the development and progression of breast cancer. Lovastatin, a hydroxmethyl coenzyme A (HMG-CoA) reductase inhibitor, inhibits breast cancer cell proliferation in vitro and has been implicated as having a role in preventing breast cancer. Recently, our laboratory has shown that lovastatin decreases ERa levels in human breast cancer MCF-7 cells. We hypothesized that this lovastatin-induced effect may be due to depletion of HMG CoA-derived isoprenoids and/or reduction of the isoprenylation of important regulatory proteins, such as those of the RAS family. MCF7 cells were incubated with increasing concentrations (0.1-50 mM) of lovastatin. ERa levels decreased in a concentration-dependant manner and were maintained at control levels with co-addition of mevalonic acid which is the immediate product of HMG CoA reductase. Lovastatin decreased ERa mRNA in a similar manner. To further define this effect, cells were treated with specific farnesyl or geranylgeranyl transferase inhibitors (FTIs/GGTIs). Incubation with either 1uM FTI- 277 (Sigma) or 20uM GGTI-286 (Sigma) did not reduce ERa levels. Strikingly, coincubation with both inhibitors (1uM FTI and 20uM GGTI reduced ERa to undetectable levels. Further studies will reveal the identity of the protein that, when its isoprenylation is impaired, results in the reduction of ERa levels.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]