In the search for differences between estrogen receptor (ER) α and ERβ, we proved that ERα but not ERβ directly interacts with calmodulin (CaM) through the hinge region. The transcriptional activity of a mutant unable to interact with CaM becomes insensitive to inhibition by CaM antagonists (W7). These residues are acetylated by p300 and substitution of lysine 302 and 303 with other residues enhance ERα-hormone sensitivity, suggesting that ERα acetylation normally suppresses ligand sensitivity. Also, the somatic mutation K303R has been identified in early premalignant breast lesions. ERα K303R normally binds E but shows increased E-induced transcriptional activation and increased proliferation in response to E when transfected into breast cancer cell (BC) lines. Herein, we show that mutations K303R and K303A, render an ERα unable to interact with CaM and therefore insensitive to W7. K303 homodimers and K303 mutant/wt heterodimers show increased sensitivity to E. Contrary to the wt ERα, AP1 transcriptional activity is inhibited by estradiol (E2) and OH-Tamoxifen (OH-TAM) in both K303R and K303A mutants.