Modulation of estrogen receptor alpha 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 (ERalpha). Because a switch from ligand-dependent to ligand-independent activation of ERalpha-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 ERalpha, 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 ERalpha expression and survival function in human breast cancer cells. The DBC-1 amino terminus binds directly to the ERalpha 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 (7alpha,17beta-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol) disrupt the DBC-1/ERalpha interaction, thus revealing the DBC-1/ERalpha 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 ERalpha protein, suggesting that DBC-1 may stabilize unliganded ERalpha by virtue of their direct association. Finally, DBC-1 depletion promotes hormone-independent apoptosis of ERalpha-positive, but not ERalpha-negative, breast cancer cells in a manner reversible by endocrine agents that disrupt the DBC-1/ERalpha interaction. Collectively, these findings establish a principal biological function for DBC-1 in the modulation of ERalpha expression and hormone-independent breast cancer cell survival.
Trauernicht
Amy M
AM
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA.
Kim
Se Jin
SJ
Kim
Nam Hee
NH
Boyer
Thomas G
TG
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D017931:DNA Primers; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D008024:Ligands; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering