Modulation of estrogen receptor α protein level and survival function by DBC-1

Acquired resistance to endocrine therapy represents a major clinical obstacle to the successful management of estrogen-dependent breast cancers expressing estrogen receptor alpha (ER alpha). Because a switch from ligand-dependent to ligand-independent activation of ER alpha-regulated breast cancer cell growth and survival may define a path to endocrine resistance, enhanced mechanistic insight concerning the ligand-independent fate and function of ER alpha, including a more complete inventory of its ligand-independent cofactors, could identify novel markers of endocrine resistance and possible targets for therapeutic intervention in breast cancer. Here, we identify the deleted in breast cancer 1 gene product DBC-1 (KIAA1967) to be a principal determinant of unliganded ER alpha expression and survival function in human breast cancer cells. The DBC-1 amino terminus binds directly to the ER alpha hormone-binding domain both in vitro and in vivo in a strict ligand-independent manner. Furthermore, like estrogen, the antiestrogens tamoxifen and ICI 182,780 (7 alpha, 17 beta-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol) disrupt the DBC-1/ER alpha interaction, thus revealing the DBC-1/ER alpha interface to be a heretofore-unrecognized target of endocrine compounds commonly used in hormonal therapy. Notably, RNA interference-mediated DBC-1 depletion reduces the steady-state level of unliganded but not liganded ER alpha protein, suggesting that DBC-1 may stabilize unliganded ER alpha by virtue of their direct association. Finally, DBC-1 depletion promotes hormone-independent apoptosis of ER alpha-positive, but not ER alpha- negative, breast cancer cells in a manner reversible by endocrine agents that disrupt the DBC1/ER alpha interaction. Collectively, these findings establish a principal biological function for DBC-1 in the modulation of ER alpha expression and hormone-independent breast cancer cell survival.