Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long 
been a therapeutic choice for all stages of estrogen receptor (ER)-positive 
breast cancer. The clinical application of long-term adjuvant antihormone 
therapy for the breast cancer has significantly improved breast cancer survival. 
However, acquired resistance to SERM remains a significant challenge in breast 
cancer treatment. The evolution of acquired resistance to SERMs treatment was 
primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic 
years of adjuvant treatment in patients. Acquired resistance to tamoxifen is 
unique because the growth of resistant tumors is dependent on SERMs. It appears 
that acquired resistance to SERM is initially able to utilize either E2 or a 
SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic 
studies reveal that SERMs continuously suppress nuclear ER-target genes even 
during resistance, whereas they function as agonists to activate multiple 
membrane-associated molecules to promote cell growth. Laboratory observations in 
vivo further show that three phases of acquired SERM-resistance exists, 
depending on the length of SERMs exposure. Tumors with Phase I resistance are 
stimulated by both SERMs and estrogen. Tumors with Phase II resistance are 
stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The 
laboratory models suggest a new treatment strategy, in which limited-duration, 
low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. 
This discovery provides an invaluable insight into the evolution of drug 
resistance to SERMs, and this knowledge is now being used to justify clinical 
trials of estrogen therapy following long-term antihormone therapy. All of these 
results suggest that cell populations that have acquired resistance are in 
constant evolution depending upon selection pressure. The limited availability 
of growth stimuli in any new environment enhances population plasticity in the 
trial and error search for survival.