The majority of breast cancers are estrogen receptor (ER) positive and depend on 
estrogen for growth. Therefore, blocking estrogen mediated actions remains the 
strategy of choice for the treatment and prevention of breast cancer. The 
selective estrogen receptor modulators (SERMs) are molecules that block estrogen 
action in breast cancer, but can still potentially maintain the beneficial 
effects of estrogen in other tissues, such as bone and cardiovascular system. 
Tamoxifen, the prototypical drug of this class has been used extensively for the 
past 30 years to treat and prevent breast cancer. The target of drug action, ERs 
alpha and beta, are the two receptors which are responsible for the first step 
in estrogen and SERM action. The SERM binds to the ERs and confers a unique 
conformation to the complex. In a target site which expresses antiestrogenic 
actions, the conformation of the ER is distinctly different from estrogen bound 
ER. The complex recruits protein partners called corepressors to prevent the 
transcription of estrogen responsive genes. In contrast, at a predominantly 
estrogenic site coactivators for estrogen action are recruited. Unfortunately at 
an antiestrogenic site such as breast cancer, long term SERM therapy causes the 
development of acquired resistance. The breast and endometrial tumor cells 
selectively become SERM stimulated. Overexpression of receptor tyrosine kinases, 
HER-2, EGFR and IGFR and the signaling cascades following their activation are 
frequently involved in SERM resistant breast cancers. The aberrantly activated 
PI3K/AKT and MAPK pathways and their cross talk with the genomic components of 
the ER action are implicated in SERM resistance. Other down stream factors of 
HER-2 and EGFR signaling, such as PI3K/AKT, MAPK or mTOR pathways has also been 
found to be involved in resistance mechanisms. Blocking the actions of HER-2 and 
EGFR represent a rational strategy for treating SERM resistant phenotypes and 
may in fact restore the sensitivity to the SERMs. Another approach exploits the 
discovery that low dose estrogen will induce apoptosis in the SERM resistant 
breast cancers. Numerous clinical studies are addressing these issues.