This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 21/7/1526    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Trauernicht, A. M. Articles by Boyer, T. G. Search for Related Content PubMed PubMed Citation Articles by Trauernicht, A. M. Articles by Boyer, T. G.

Modulation of Estrogen Receptor Protein Level and Survival Function by DBC-1

Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245

Address all correspondence and requests for reprints to: Thomas G. Boyer, Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245-3207. E-mail: boyer{at}uthscsa.edu.

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

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol  |  Fulvestrant