Selective estrogen receptor modulators (SERMs) such as tamoxifen
are effective in the treatment of many estrogen receptor-positive
breast cancers and have also proven to be effective in the prevention
of breast cancer in women at high risk for the disease. The comparative
abilities of tamoxifen versus raloxifene in breast cancer prevention
are currently being compared in the Study of Tamoxifen and Raloxifene
trial. To better understand the actions of these compounds in
breast cancer, we have examined their effects on the expression
of approximately 12,000 genes, using Affymetrix GeneChip microarrays,
with quantitative PCR verification in many cases, categorizing
their actions as agonist, antagonist, or partial agonist/antagonist.
Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen
(TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol
(E2) in estrogen receptor-containing MCF-7 human breast cancer
cells revealed that (a) TOT was the most E2-like of the three
compounds, (b) all three compounds either partially or fully antagonized
the action of E2 on most genes, with the order of antagonist activity
being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed
partial agonist/partial antagonist activity on a number of E2-regulated
genes, (d) several stimulatory cell cycle-related genes were down-regulated
exclusively by ICI, (e) the estrogen-like activity of Ral nearly
always overlapped with that of TOT, indicating that Ral has little
unique agonist activity different from that of TOT, and (f) some
genes were specifically up-regulated by TOT but not Ral, ICI,
or E2. Hence, gene expression profiling can discern fundamental
differences among SERMs and provides insight into the distinct
biologies of TOT, Ral, and ICI in breast cancer.