This Article Full Text Full Text (PDF) Supplemental Data 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 Request Copyright Permission Citing Articles Citing Articles via HighWire 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. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene

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

This article has been cited by other articles:

				E. J. Cha, S. J. Noh, K. S. Kwon, C. Y. Kim, B.-H. Park, H. S. Park, H. Lee, M. J. Chung, M. J. Kang, D. G. Lee, et al. Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma Clin. Cancer Res., July 1, 2009; 15(13): 4453 - 4459. [Abstract] [Full Text] [PDF]

				S. Garapaty, C.-F. Xu, P. Trojer, M. A. Mahajan, T. A. Neubert, and H. H. Samuels Identification and Characterization of a Novel Nuclear Protein Complex Involved in Nuclear Hormone Receptor-mediated Gene Regulation J. Biol. Chem., March 20, 2009; 284(12): 7542 - 7552. [Abstract] [Full Text] [PDF]

				J. Fu, J. Jiang, J. Li, S. Wang, G. Shi, Q. Feng, E. White, J. Qin, and J. Wong Deleted in Breast Cancer 1, a Novel Androgen Receptor (AR) Coactivator That Promotes AR DNA-binding Activity J. Biol. Chem., March 13, 2009; 284(11): 6832 - 6840. [Abstract] [Full Text] [PDF]