Effects of LY117018 (a SERM analog of raloxifene) on tumor suppressor proteins and proliferation of breast cancer cells.

We have previously shown that presence of estradiol (E2) in the growth medium causes (i) proliferation of T47D breast cancer cells, (ii) elevation of p53 levels, and (iii) hyperphos-phorylation of retinoblastoma protein (pRb). In the present study, we examined the expression of p53, phosphorylation state of pRb and proliferation of T47D cells in the presence of LY117018 (Courtesy of Lilly Research Laboratories), an analog of raloxifene, which is a known selective estrogen receptor modulator (SERM). The cells grown in charcoal-treated serum were treated with 1 nM E2 or different concentrations of LY117018 for 24 h. E2 or LY117018 treatments caused a 2- to 3-fold increase in the level of p53 and hyperphosphorylation of pRb. E2 treatment increased cell proliferation, whereas LY117018 treatment had no such effect but inhibited the E2-dependent cell proliferation. E2 and LY117018 treatments of T47D cells also caused differential effects on intracellular structures. Thus, LY117018 treatment induces changes in the level/activity of p53 and pRb and ultrastructure of T47D cells. Importantly, LY11708 inhibits estrogen-induced cell proliferation while mimicking E2 actions on p53 induction and pRb phosphorylation. The SERM also induced structural alterations in the T47D cells.