Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells.

Estrogen receptors play a key role in breast cancer development. One of the current therapeutic strategies for the treatment of estrogen receptor (ER)-α-positive breast cancers relies on the blockade of ERα transcriptional activity. In the present study, we characterized Hakai, originally characterized as an E-cadherin binding protein, as a strong blockade of ERα in breast cancer cells. We showed that Hakai inhibited the transcriptional activity of ERα by binding directly to ERα. The DNA-binding domain of ERα was found to be responsible for its interaction with Hakai. Hakai competed with ERα coactivators, such as steroid receptor coactivator-1 (SRC-1) and glucocoriticord receptor interacting protein-1 (GRIP-1), for the modulation of ERα transactivation, while its ubiquitin-ligase activity was not required. Further, overexpression of Hakai inhibited the proliferation and migration of breast cancer cells. Taken together, these results suggest that Hakai is a novel corepressor of ERα and may play a negative role in the development and progression of breast cancers.