Tamoxifen is the standard first-line hormonal therapy for premenopausal women 
with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the 
crucial mechanisms underlying hormonal therapy resistance is the collateral 
activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored 
whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of 
tamoxifen against ER-positive BC cells. We have observed a synergism between 
alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell 
lines harboring different PI3K alterations. Immunoblotting analysis showed 
alpelisib, buparlisib, or either drug in combination with tamoxifen 
downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the 
MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 
construct or mutant ER, the synergistic effect between alpelisib and tamoxifen 
was markedly attenuated, indicating that synergism depends on AKT inhibition or 
normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also 
attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that 
additional PI3K blockade might be effective in enhancing the therapeutic effect 
of tamoxifen in ER-positive BC and support the rationale combination in clinical 
trials.