Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes

Abstract

Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein͞coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR-and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.Nuclear receptors are structurally related, ligand-activated regulators of a complex array of genes involved in cell proliferation, differentiation, morphogenesis, and homeostasis (1, 2). In the absence of ligand, several nuclear receptors associate with a nuclear receptor corepressor (N-CoR) (3-6) or the related factor SMRT (silencing mediator of retinoid and thyroid receptors) (7) to mediate repression. Their regulatory function is further modulated by both physiologic and pharmacologic ligands and by the actions of various signal transduction pathways that result in ligand-independent gene activation of diverse nuclear receptor family members (8)(9)(10).N-CoR and SMRT appear to be components of cellular complexes (4, 11, 12) containing histone deacetylases (HDACs) (13, 14) and homologs of the yeast repressor Sin3 (15, 16), which are recruited to DNA via targeting by diverse DNA-binding, site-specific transcription factors (reviewed in refs. 17 and 18). Conversely, transcriptional activation by nuclear hormone receptors requires the ligand-dependent association of a coactivator complex that includes a family of nuclear receptor coactivators (NCoAs) (19-23) and also includes the histone acetylases Creb-binding protein (CBP)͞ p300 (24-28) and P͞CAF (29,50).The development of inhibitory ligands for the nuclear receptors has yielded important therapeutic treatments, among them the use of tamoxifen for endocrine therapy of breast cancer (reviewed in refs. 10 and 30). However, in certain tissues such as uterus and bone, and after long-term treatment in patients with breast cancer, tamoxifen exhibits unexplained partial agonistic activity (31). Various agents that raise intracellular cAMP levels or stimulate the ras͞MAP kinase pathway can similarly cause estrogen receptor (ER) activation in the presence of tamoxifen or the absence of any activating ligand (9,(32)(33)(34)(35). In this manuscript we show that diverse molecular strategies regulate the association of N-CoR-or SMRT-containing complexes with specific nuclear receptors, including the nature of the ligand, the levels of available N-CoR͞SMRT, and the action of diverse protein ki...

Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer

“…Furthermore, other factors can affect protein activity for example phosphorylation in the case of AIB1 (Mora and Brown, 2000) or sequestration by other proteins such as prothymosinalpha in the case of ROA (Martini et al, 2000). Our studies do not exclude differences at the protein and/or activity levels of ROA and AIB1 being involved in de novo tamoxifen resistance, nor do they exclude altered expression of these factors having a role in acquired tamoxifen resistance (Lavinsky et al, 1998). Altogether, there is little evidence for altered coregulators expression in breast tumours that are de novo tamoxifen resistant.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Low expression of NCOR1 is associated with shorter relapse-free survival in breast cancer patients, which shows that loss of NCOR1 enhances breast cancer development [194]. Further, decrease in NCOR1 protein expression correlates with acquired tamoxifen resistance in a mouse model of breast cancer [195]. Both scaffold attachment factor B (SAFB) 1 and SAFB2 suppress ERα target gene expression in breast cancer cells by associating with NCOR1 [196].…”

Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

“…2), previously associated with increased ER activity were found to be higher in MLET5 cells than in MCF-7 cells, with the higher levels of phosphorylation reflecting the elevated ER expression in MLET5 cells. Alternatively, altered ER transcriptional co-regulator levels could lead to attenuation of expression of regulated genes [18][19][20]. Although expression of the p160 co-activators of ER SRC1 and AIB1…”