The classic steroid hormone estrogen mediates its biological effects in cells through the estrogen receptor (ER), a member of the nuclear receptor family. ER is an intracellular transcription factor composed of six domains. Estrogen binding to the ER promotes its dimerization and nuclear localization. There, activated ER binds to DNA sequences, termed estrogen response elements (EREs), in the regulatory regions of target genes. Several factors, including coactivators, corepressors and integrator proteins are important in ER-mediated transcription. It is becoming apparent that transcriptional regulation requires the recruitment by ER of multiple, distinct proteins that co-operate to achieve the required response.
Calmodulin, a ubiquitous modulator of Ca2+ signaling, regulates the function of multiple, diverse proteins. Accumulating evidence supports a role for Ca2+ and calmodulin in breast carcinoma, as well as in estrogen action. Calmodulin contributes to the regulation of both ER-mediated transcriptional activation and ER degradation. For example, calmodulin binds directly to ER in a Ca2+-dependent manner and is required for formation of the ER-ERE complex. Evidence from our laboratory indicates that endogenous ER binds to endogenous calmodulin, attenuating the degradation of ER by sequestering it away from the ubiquitin degradation pathway. We subsequently documented that an interaction between calmodulin and ER in the nucleus is required for estrogen-stimulated ER transcriptional activation. Together with the report that calmodulin antagonists inhibit the growth of human breast carcinoma cell lines, these findings suggest that Ca2+/calmodulin may be an important component of ER signaling pathways.