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

Amy M. Trauernicht, Jin Kim Se, Hee Kim Nam, Thomas G. Boyer

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Acquired resistance to endocrine therapy represents a major clinical obstacle to the successful management of estrogen-dependent breast cancers expressing estrogen receptor α (ERα). Because a switch from ligand-dependent to ligand-independent activation of ERα-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 ERα, 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 ERα expression and survival function in human breast cancer cells. The DBC-1 amino terminus binds directly to the ERα 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 (7α,17β-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3, 5(10)-triene-3,17-diol) disrupt the DBC-1/ERα interaction, thus revealing the DBC-1/ERα 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 ERα protein, suggesting that DBC-1 may stabilize unliganded ERα by virtue of their direct association. Finally, DBC-1 depletion promotes hormone-independent apoptosis of ERα-positive, but not ERα-negative, breast cancer cells in a manner reversible by endocrine agents that disrupt the DBC-1/ERα interaction. Collectively, these findings establish a principal biological function for DBC-1 in the modulation of ERα expression and hormone-independent breast cancer cell survival.

Original languageEnglish (US)
Pages (from-to)1526-1536
Number of pages11
JournalMolecular Endocrinology
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 1 2007

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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