Significance

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. We now show that calcineurin, a Ca ²⁺ -dependent protein phosphatase, plays a previously unrecognized role in the regulation of ER-α stability and activity. Calcineurin stabilizes ER-α by mediating its dephosphorylation at Ser ²⁹⁴ and thereby preventing its degradation by the ubiquitin–proteasome pathway. Calcineurin mediates ER-α activation by promoting its phosphorylation at Ser ¹¹⁸ by mTOR. A high level of calcineurin gene expression was also found to be associated with a poor prognosis of ER-α–positive breast cancer patients treated with endocrine therapeutic agents. We therefore propose that the selective inhibition of calcineurin might be an effective approach to the treatment of ER-α–positive breast cancer.