NR2F6

Gene Summary

Gene:NR2F6; nuclear receptor subfamily 2 group F member 6
Aliases: EAR2, EAR-2, ERBAL2
Location:19p13.11
Summary:-
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor subfamily 2 group F member 6
Source:NCBIAccessed: 30 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • CD4-Positive T-Lymphocytes
  • Non-Small Cell Lung Cancer
  • TNF
  • POLR2A RNA polymerase, human
  • Cell Survival
  • T-Lymphocytes
  • MicroRNAs
  • Receptors, Steroid
  • Cancer Gene Expression Regulation
  • Orphan Nuclear Receptors
  • Antineoplastic Agents, Immunological
  • Immunologic Surveillance
  • Apoptosis
  • Immunoblotting
  • Single Nucleotide Polymorphism
  • Genetic Association Studies
  • Mice, Inbred BALB C
  • Leukaemia
  • Nr2f6 protein, mouse
  • Signal Transduction
  • Lung Cancer
  • Immunotherapy
  • X-Linked Inhibitor of Apoptosis Protein
  • Molecular Targeted Therapy
  • Binding Sites
  • Immunomodulation
  • Cell Cycle
  • Cell Differentiation
  • COUP Transcription Factors
  • Interferon-gamma
  • Prostate Cancer
  • Polymerase Chain Reaction
  • NR2F6
  • RTPCR
  • Chromosome 19
  • Programmed Cell Death 1 Receptor
  • Disease-Free Survival
  • Cytokines, Interleukin-2
  • Immunotherapy, Adoptive
  • CTLA-4 Antigen
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: NR2F6 (cancer-related)

Iljin A, Antoszewski B, Durko M, et al.
External auditory meatus and/or conchal bowl reconstruction with postauricular island flap in patients with Basal Cell Carcinoma or Squamous Cell Carcinoma.
Otolaryngol Pol. 2018; 72(3):4-10 [PubMed] Related Publications
AIMS: Presenting our clinical experience with the postauricular island flap (pif) and estimation of the results following partial external auditory canal (eac) and/or auricular conchal bowl reconstructions with the pif in patients after carcinoma resections.
METHODS: We have analyzed postoperative results of 19 patients after auricular conchal bowl (11), or auricular conchal bowl and eac (8) reconstructions with pif, following malignant tumor resections, between 2000-2015. The patients were followed-up and evaluated in respect of early and long-term results after surgical treatment considering plastic surgeon's and patient's opinion.
RESULTS: The cancers were completely excised in all patients, and there were no recurrences within at least 2 years of follow-up. The observed complications after reconstructions comprised venous congestion in five cases (26.3 %), pinning of the operated ear in four patients (21 %), prominent earlobe in three (15.8 %), and eac constriction in three cases (15.8 %). Postoperative result was very good in all cases (both in the opinion of plastic surgeon and patients), except patients with pinning of the operated ear, prominent earlobe (moderately satisfied). Conclusions 1. Combined operations involving postauricular island flap reconstructions after partial (external auditory meatus and/or auricular conchal bowl) resections allowed for complete removal of malignant tumors with no evidence of recurrence, and also preservation of proper conchal shape in the reconstructed ear. 2. Retroauricular approach in cases with cancer involvement of the external auditory meatus allowed for proper visualization and estimation of lesions extent, as well as adequate surgical access.

Ronen S, Gru AA, Noland MM, et al.
Cutaneous Squamous Cell Carcinoma With Sclerosing Features: An Uncommon and Potentially Aggressive Variant.
Am J Dermatopathol. 2018; 40(8):575-579 [PubMed] Related Publications
Sclerosing squamous cell carcinoma (SCC), also known as "desmoplastic" SCC, is a rare subtype of cutaneous malignancy. This variant is clinically significant because it is associated with an increased risk of local recurrence and metastasis. We herein present 16 examples of sclerotic SCC of the skin in 8 men and 3 women, with a median age of 66 years. The most common site of origin for this tumor is the skin of the head and neck, including the scalp (5 tumors in 2 different patients), forehead (3 cases), nasal ala (2 cases), neck (2 cases in the same patient), ear (2 cases), cheek (1 case), and chest (1 case). Microscopically, sclerosing SCCs are characterized by cellular cords, nests, and islands, as well as scattered single cells infiltrating densely desmoplastic and collagenized connective tissue. The differential diagnosis principally includes sclerosing basal cell carcinoma, microcystic adnexal carcinoma, and desmoplastic trichoepithelioma. The main goals of this study are to further characterize these lesions pathologically, and increase general awareness of this SCC subtype.

Klepsch V, Hermann-Kleiter N, Do-Dinh P, et al.
Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade.
Nat Commun. 2018; 9(1):1538 [PubMed] Free Access to Full Article Related Publications
Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6, particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progression and improves survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade reveal multiple advantageous transcriptional alterations. Acute Nr2f6 silencing in both mouse and human T cells induces hyper-responsiveness that establishes a non-redundant T-cell-inhibitory function of NR2F6. NR2F6 protein expression in T-cell-infiltrating human NSCLC is upregulated in 54% of the cases (n = 303) and significantly correlates with PD-1 and CTLA-4 expression. Our data define NR2F6 as an intracellular immune checkpoint that suppresses adaptive anti-cancer immune responses and set the stage for clinical validation of targeting NR2F6 for next-generation immuno-oncological regimens.

Yoo SS, Hong MJ, Lee JH, et al.
Association between polymorphisms in microRNA target sites and survival in early-stage non-small cell lung cancer.
Thorac Cancer. 2017; 8(6):682-686 [PubMed] Free Access to Full Article Related Publications
A high-throughput mapping method of RNA-RNA interactions by crosslinking, ligation, and sequencing of hybrids (CLASH) can not only provide information about canonical but also non-canonical interactions. We evaluated the associations between variants in microRNA target sites using CLASH data and survival outcomes of 782 early-stage non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Among the 100 variants studied, two variants showed significant association with survival outcomes. The POLR2A rs2071504 C > T variant was associated with poor overall and disease-free survival under a dominant model (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08-1.88; P = 0.01 and HR 1.34, 95% CI 1.08-1.67; P = 0.01, respectively). Patients carrying the NR2F6 rs2288539 TT genotype showed significantly better overall survival than those with the NR2F6 rs2288539 CC or CT genotypes (HR 0.13, 95% CI 0.02-0.90; P = 0.04). These findings suggest that POLR2A rs2071504 C > T and NR2F6 rs2288539 C > T can influence prognosis in early-stage NSCLC patients.

Tao Z, Li S, Ichim TE, et al.
Cellular immunotherapy of cancer: an overview and future directions.
Immunotherapy. 2017; 9(7):589-606 [PubMed] Related Publications
The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.

Liu J, Li T, Liu XL
DDA1 is induced by NR2F6 in ovarian cancer and predicts poor survival outcome.
Eur Rev Med Pharmacol Sci. 2017; 21(6):1206-1213 [PubMed] Related Publications
OBJECTIVE: In this study, we investigated the dysregulated genes in ovarian cancer epithelial cells (CEPIs) compared to normal ovarian surface epithelia (OSE). The mechanism of co-upregulation between NR2F6 and DDA1 in CEPIs and their association with survival outcomes were further studied.
MATERIALS AND METHODS: The microarray that assessed gene expression profiles of ovarian CEPIs was searched in GEO datasets. The genes co-expressed with NR2F6 in the ovarian cohort in TCGA database were identified and analyzed using cBioportal and UCSC Xena. The association between NR2F6, DDA1 and overall survival (OS) and recurrence free survival (RFS) in ovarian cancer patients were assessed using Kaplan-Meier Plotter. The regulative effect of NR2F6 on DDA1 expression was verified by qRT-PCR, Western blotting and dual luciferase assay.
RESULTS: NR2F6 is significantly upregulated in CEPIs compared to OSE. High NR2F6 expression is associated with significantly worse OS (HR: 1.22, 95% CI: 1.07-1.4, p=0.0039, N=1656). NR2F6 and DDA1 are co-upregulated in ovarian cancer (Pearson's r=0.57). NR2F6 overexpression resulted in significantly upregulated DDA1 expression at both mRNA and protein levels in SKOV3 and A2780 cells. DDA1 promoter contains a NR2F6 binding site between -349 and -336 upstream the TSS site. High DDA1 expression is associated with significantly shorter RFS (HR: 1.38, 95% CI: 1.12-1.69, p=0.0023, N=614).
CONCLUSIONS: NR2F6 and DDA1 are co-upregulated in ovarian cancer. High NR2F6 expression is associated with significantly worse OS. NR2F6 can activate DDA1 transcription via binding to the DDA1 promoter. DDA1 upregulation is associated with significantly worse RFS among the ovarian cancer patients.

Iljin A, Lewandowicz E, Antoszewski B, et al.
Results of Auricular Conchal Bowl Reconstructions Following Cancer Resections with Postauricular Island Flap.
Pol Przegl Chir. 2016; 88(6):315-320 [PubMed] Related Publications
The aim of the study was to present our experience with the postauricular island flap (pif) and clinical evaluation of the results following auricular conchal bowl reconstructions with the pif in patients after carcinoma resections.
MATERIAL AND METHODS: We analyzed results in 13 patients who underwent auricular conchal bowl reconstructions with pif following malignant tumor resection between 2000-2013. The patients were followed-up. We estimated early and long-term results after surgery including plastic surgeon's and patient's opinion.
RESULTS: The malignancies were completely excised in all patients, and there were no recurrences within 2 years of follow-up. Observed complications of conchal bowl reconstructions were venous congestion in two cases (15.3 %), and pinning of the operated ear in two patients (15.3%). Postoperative result was very good in 11 cases (both in the opinion of plastic surgeon and patients), whereas in two patients with pinning of the operated ear was satisfied.
CONCLUSIONS: 1. Postauricular island flap reconstructions after auricular conchal bowl resections allowed for complete removal of malignant tumors with no evidence of recurrence, and also preserved proper conchal shape in the reconstructed ear. 2. Reconstructions of auricular conchal bowl with the postauricular island flap resulted in very good postoperative results, which confirms the efficiency of the applied technique. 3. Reconstructive surgery with postauricular island flap of individuals with partial auricular conchal bowl defects contributed to postoperative satisfaction in both patients and doctors' estimations.

Shin DH, Kwon GS
Epothilone B-based 3-in-1 polymeric micelle for anticancer drug therapy.
Int J Pharm. 2017; 518(1-2):307-311 [PubMed] Free Access to Full Article Related Publications
Epothilones are microtubule inhibitors that are promising alternatives to paclitaxel due to enhanced anticancer efficacy. While epothilones are slightly more water soluble than paclitaxel and more active against paclitaxel-resistant cells, they still require formulation with Cremophor EL and/or cosolvents and drug resistance still limits therapeutic efficacy. In this report, we showed that the combinational treatment of epothilone B (EpoB), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG, Hsp90 inhibitor), and rapamycin (mTOR inhibitor) displays strong anticancer activity in vitro and in vivo. To address the poor water solubility of this 3 drug-combination, they were co-loaded into poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles, and the 3-in-1 loaded PEG-b-PLA micelle (m-EAR) was characterized in terms of drug loading efficiency, particle size, release kinetics. The m-EAR achieved high levels of all three drugs in water; formed micelles with hydrodynamic diameters at ca. 30nm and released the drugs in a sustained manner in vitro at rates slower than individually loaded PEG-b-PLA micelles. In A549-derived xenograft mice, m-EAR (2.0, 15.0, and 7.5mg/kg) caused tumor regression after four weekly injections, whereas EpoB alone (2.0mg/kg) was the same as control. No severe changes in body weight relative to PBS control were observed, attesting to the safety of m-EAR. Collectively, these results suggest that m-EAR provides a simple, but effective and safe EpoB-based combination nanomedicine for cancer therapy.

Niu C, Sun X, Zhang W, et al.
NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer.
Int J Mol Sci. 2016; 17(10) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer.
METHODS: NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined.
RESULTS: There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (
CONCLUSIONS: Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer.

Klepsch V, Hermann-Kleiter N, Baier G
Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy.
Immunol Lett. 2016; 178:31-6 [PubMed] Related Publications
Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector immune cells. Targeting these alternative checkpoints in cancer immunotherapy with the goal to strengthen the patient's immune system are likely to extend the benefits of cancer immunotherapy in the near future. Along this line, we have defined and validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) as an intracellular immune checkpoint in effector T cells. NR2F6 acts as a novel master switch of antitumor responses against both transplantable and spontaneous tumors in mice relevant for human cancer. NR2F6 directly represses transcription of key cytokine genes in T effector cells relevant for tumor cell rejection, such as IL-2, IFN and TNFα. Thus, in the presence of NR2F6, T cell activation is limited within the tumor microenvironment. This defines NR2F6 as a key checkpoint governing the amplitude of cancer immune surveillance. Based on our study, an approach shall be initiated to identify low molecular weight compounds that selectively interfere with NR2F6 function in the clinic.

Hermann-Kleiter N, Klepsch V, Wallner S, et al.
The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.
Cell Rep. 2015; 12(12):2072-85 [PubMed] Free Access to Full Article Related Publications
Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6(-/-) mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4(+) and CD8(+) T cells and higher expression levels of interleukin 2 and interferon γ at the tumor site. Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.

Couto JA, Greene AK
Management of problematic infantile hemangioma using intralesional triamcinolone: efficacy and safety in 100 infants.
J Plast Reconstr Aesthet Surg. 2014; 67(11):1469-74 [PubMed] Related Publications
BACKGROUND: Intralesional corticosteroid is one method used to limit the rapid growth of infantile hemangiomas. The purpose of this study was to determine the efficacy and safety of triamcinolone injection using a standardized protocol.
METHODS: The study comprised infants managed with intralesional corticosteroid between 2007 and 2013. Tumors ≤3 cm in diameter were injected with triamcinolone, not to exceed 3 mg/kg, and followed every 4-6 weeks to determine whether additional injections were indicated. Predictive variables were patient age and tumor location, depth, and size. Treatment response was defined as regression, stabilization, or failure. Rebound growth and drug morbidity were recorded.
RESULTS: Seventy-three females and 27 males had lesions located on the lip (29%), cheek (20%), nose (16%), periorbital area (13%), forehead (7%), scalp (4%), chin (2%), ear (2%), trunk (2%), extremity (2%), and neck (2%). Mean tumor size was 2.1 cm(2) (range 0.15-9.0). Treatment began at an average age of 11 weeks (range 3-30). The mean number of injections was 1.8 (range 1-5), and the average dose per injection was 1.6 mg/kg (range 0.76-2.66). All tumors responded: 63% regressed and 37% stabilized. Rebound growth affected 40% of tumors at a median of 3 weeks (IQR 3-4) following injection. Age, location, size, and depth did not affect treatment response (p = 0.7). None of the patients exhibited systemic side-effects and 2% had atrophy at the site of injection.
CONCLUSION: Intralesional triamcinolone is an effective treatment for small, localized proliferating infantile hemangiomas. Therapy is safe and infants are at minimal risk for systemic side-effects when low doses of corticosteroid are used.

Mond M, Alexiadis M, Eriksson N, et al.
Nuclear receptor expression in human differentiated thyroid tumors.
Thyroid. 2014; 24(6):1000-11 [PubMed] Related Publications
BACKGROUND: Nuclear receptors (NRs) play a key role in endocrine signaling and metabolism and are important therapeutic targets in a number of hormone-dependent malignancies. Studies on the role of NRs in thyroid cancer are limited.
OBJECTIVE: The objective of the study was to examine systematically the expression of the 48 human NRs in a series of benign and malignant thyroid tissues. Within the papillary carcinoma cohort, we sought to determine if NR expression differed significantly by BRAF mutation status.
PATIENTS AND METHODS: RNA was isolated from multinodular goiter (MNG; n=6), papillary carcinoma (PTC, n=14), follicular carcinoma (FC; n=5), and Hürthle cell carcinoma (HCC; n=7). The 48 human NRs were profiled in this panel by quantitative real time polymerase chain reaction. Protein expression for selected NRs (Rev-erbα and LXR-β) was examined by immunohistochemistry (IHC) on tissue microarrays comprising benign and malignant thyroid tissues.
RESULTS: Across all groups of benign and malignant thyroid tissue, there was prominent expression of LXR-β and ROR-γ. Key findings in PTC were marked overexpression of RXR-γ and Rev-erbα compared to MNG. Within the PTC cohort, when BRAF(V600E) tumors were compared with wild type BRAF, there was relative upregulation of RXR-γ and Rev-erbα and downregulation of AR, ERR-γ, and ROR-γ. In FC, EAR-2 was overexpressed, while PPAR-α and PPAR-δ were underexpressed compared to MNG. The NR expression profile of HCC was distinct, characterized by significant downregulation of a wide range of NRs. IHC for Rev-erbα and LXR-β localized protein expression to the tumor cells. Moderate to strong Rev-erbα immunostaining was seen in 22 out of 23 PTC, and, overall, staining was stronger than in the benign group.
CONCLUSIONS: These results represent the first systematic examination of NR expression in thyroid cancer. Our finding of tumor-specific patterns of NR expression, as well as significant differences in NR expression between BRAF(V600E) and wild type BRAF PTC, provides a basis for further mechanistic studies and highlights potential novel therapeutic targets for this malignancy.

Safe S, Jin UH, Hedrick E, et al.
Minireview: role of orphan nuclear receptors in cancer and potential as drug targets.
Mol Endocrinol. 2014; 28(2):157-72 [PubMed] Free Access to Full Article Related Publications
The nuclear orphan receptors for which endogenous ligands have not been identified include nuclear receptor (NR)0B1 (adrenal hypoplasia congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbα/β), NR2C1 (testicular receptor 2), NR2C2 (testicular receptor 4), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (v-erbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1), NR4A3 (Nor1), and NR6A1 (GCNF). These receptors play essential roles in development, cellular homeostasis, and disease including cancer where over- or underexpression of some receptors has prognostic significance for patient survival. Results of receptor knockdown or overexpression in vivo and in cancer cell lines demonstrate that orphan receptors exhibit tumor-specific pro-oncogenic or tumor suppressor-like activity. For example, COUP-TFII expression is both a positive (ovarian) and negative (prostate and breast) prognostic factor for cancer patients; in contrast, the prognostic activity of adrenal hypoplasia congenita critical region on chromosome X gene for the same tumors is the inverse of COUP-TFII. Functional studies show that Nur77 is tumor suppressor like in acute leukemia, whereas silencing Nur77 in pancreatic, colon, lung, lymphoma, melanoma, cervical, ovarian, gastric, and some breast cancer cell lines induces one or more of several responses including growth inhibition and decreased survival, migration, and invasion. Although endogenous ligands for the orphan receptors have not been identified, there is increasing evidence that different structural classes of compounds activate, inactivate, and directly bind several orphan receptors. Thus, the screening and development of selective orphan receptor modulators will have important clinical applications as novel mechanism-based agents for treating cancer patients overexpressing one or more orphan receptors and also for combined drug therapies.

Muscat GE, Eriksson NA, Byth K, et al.
Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.
Mol Endocrinol. 2013; 27(2):350-65 [PubMed] Free Access to Full Article Related Publications
To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERα, EAR2, NUR77, TRα, and RARγ) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRβ, NUR77, RORγ, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRβ, PPARγ, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.

Li XB, Jiao S, Sun H, et al.
The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells.
Cancer Lett. 2011; 309(2):137-44 [PubMed] Related Publications
EAR2 is a member of the chick ovalbumin upstream promoter-transcription factors (COUP-TFs). COUP-TFs belong to orphan nuclear receptors and regulate many biological processes. Little is known regarding EAR2 in cancer, though much progress has been made in understanding the function of other COUP-TF members. The aim of this study is to investigate the expression and possible function of EAR2 in colorectal cancer. We determined expression of EAR2 in human primary colorectal malignant tumors and their paired adjacent normal colorectal tissues. We found that expression of EAR2 was upregulated in colorectal tumors. Knockdown of EAR2 induced apoptosis of colon cancer cells, suggesting that EAR2 may function to regulate survivability of colon cancer cells. In vivo tumor study demonstrated that knockdown of EAR2 inhibited the xenograft growth of colon cancer cells. We found that knockdown of EAR2 inhibited the expression of X-linked inhibitor of apoptosis protein (XIAP), suggesting that EAR2 regulates cell survivability, at least partly, through XIAP. In this manuscript, we demonstrated that expression of EAR2 was elevated in colorectal cancer and knockdown of EAR2 reduced survivability and tumor growth of colon cancer cells. Our results suggest that EAR2 plays an important role in development of colorectal cancer. The findings also suggest that EAR2 may serve as a potential therapeutic target of colorectal cancer.

Ichim CV, Atkins HL, Iscove NN, Wells RA
Identification of a role for the nuclear receptor EAR-2 in the maintenance of clonogenic status within the leukemia cell hierarchy.
Leukemia. 2011; 25(11):1687-96 [PubMed] Free Access to Full Article Related Publications
Identification of genes that regulate clonogenicity of acute myelogenous leukemia (AML) cells is hindered by the difficulty of isolating pure populations of cells with defined proliferative abilities. By analyzing the growth of clonal siblings in low passage cultures of the cell line OCI/AML4 we resolved this heterogeneous population into strata of distinct clonogenic potential, permitting analysis of the transcriptional signature of single cells with defined proliferative abilities. By microarray analysis we showed that the expression of the orphan nuclear receptor EAR-2 (NR2F6) is greater in leukemia cells with extensive proliferative capacity than in those that have lost proliferative ability. EAR-2 is expressed highly in long-term hematopoietic stem cells, relative to short-term hematopoietic stem and progenitor cells, and is downregulated in AML cells after induction of differentiation. Exogenous expression of EAR-2 increased the growth of U937 cells and prevented the proliferative arrest associated with terminal differentiation, and blocked differentiation of U937 and 32Dcl3 cells. Conversely, silencing of EAR-2 by short-hairpin RNA initiated terminal differentiation of these cell lines. These data identify EAR-2 as an important factor in the regulation of clonogenicity and differentiation, and establish that analysis of clonal siblings allows the elucidation of differences in gene expression within the AML hierarchy.

Alam M, Berg D, Bhatia A, et al.
Association between number of stages in Mohs micrographic surgery and surgeon-, patient-, and tumor-specific features: a cross-sectional study of practice patterns of 20 early- and mid-career Mohs surgeons.
Dermatol Surg. 2010; 36(12):1915-20 [PubMed] Related Publications
OBJECTIVE: To determine the number of Mohs micrographic surgery (MMS) stages per tumor taken by early- to mid-career Mohs surgeons and to assess other factors affecting number of stages.
METHODS: Statistical analysis of MMS logs of 20 representative early- to mid-career surgeons.
RESULTS: There was no difference in stages when surgeons were divided into two categories based on whether they had more than 500 cases per year or more than 5 years of experience. Similarly, when surgeons were categorized according to geographic location, there was no difference in number of stages. Anatomic location was associated with the number of stages (analysis of variance, p<.001), with the greatest number of stages for nose (2.01) and ear (2.06) lesions and the fewest for neck (1.47), back and shoulder (1.47), and lower extremity (1.33) lesions. Basal cell carcinomas required 1.92 stages (median 2.00), compared with 1.66 (median 1.00) for squamous cell carcinoma (p<.001).
CONCLUSIONS: Early- and mid-career Mohs surgeons appear to remove tumors with similar numbers of stages regardless of their experience, case volume, or geographic location. Number of stages varies with anatomic location and tumor type. The authors have indicated no significant interest with commercial supporters.

Friedman DL, Whitton J, Leisenring W, et al.
Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study.
J Natl Cancer Inst. 2010; 102(14):1083-95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages.
METHODS: The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14,359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5-56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression.
RESULTS: Among 14,359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm.
CONCLUSIONS: As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.

Okada T, Saito K, Takahashi M, et al.
En bloc petrosectomy for malignant tumors involving the external auditory canal and middle ear: surgical methods and long-term outcome.
J Neurosurg. 2008; 108(1):97-104 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to describe a method for resecting malignant tumors originating in the external auditory canal or middle ear and requiring en bloc resection of the petrous bone.
METHODS: Between 1995 and 2005, the authors performed en bloc petrosectomy for 18 malignant tumors in 9 male and 9 female patients, ranging in age from 15 to 74 years. Fourteen tumors originated in the external ear, 2 in the middle ear, and 2 in the parotid gland. The pathological entities included 15 squamous cell carcinomas, 2 adenoid cystic carcinomas, and 1 rhabdomyosarcoma. Through an L-shaped temporosuboccipital craniotomy, a medial osteotomy was created through the inner ear for tumors without extension into the inner ear (14 cases) and through the tip of the petrous bone for tumors reaching the inner ear (4 cases). Temporal dura mater in 3 patients and the base of the temporal lobe in 2 patients were included in the en bloc resection.
RESULTS: Surgical complications occurred in 5 patients (28%) with no deaths. During a mean follow-up period of 45 months, 3 patients died of tumor recurrence. Overall, 2- and 5-year survival rates were 86 and 78%, respectively. Two of three patients with dural extension and 1 of 2 with brain invasion remain alive. Two of four patients with tumor extension into the inner ear died.
CONCLUSIONS: En bloc petrosectomy is recommended for malignant tumors of the ear. It is safe and effective for lesions limited to the middle ear and may be the procedure of choice for tumors reaching the inner ear and those with dural or brain invasion.

Sakhinia E, Glennie C, Hoyland JA, et al.
Clinical quantitation of diagnostic and predictive gene expression levels in follicular and diffuse large B-cell lymphoma by RT-PCR gene expression profiling.
Blood. 2007; 109(9):3922-8 [PubMed] Related Publications
Recent microarray gene expression profiling studies have identified gene signatures predictive of outcome, so-called "indicator" genes, for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, measurement of these genes in routine practice remains difficult. We applied real-time polymerase chain reaction (PCR) to polyA cDNAs prepared from 106 archived human frozen lymph nodes (63 of FL, 25 of DLBCL, 10 reactive lymph nodes, and cases with paired samples of FL [4] and subsequent DLBCL [4]). Reverse transcription and polyA reverse transcriptase (RT)-PCR was performed, and resultant cDNA was probed by real-time PCR for 36 candidate indicator genes, selected from microarray studies. Nine genes showed statistically significant different expression between FL and DLBCL, including cyclin B, COL3A1, NPM3, H731, PRKCB1, OVGL, ZFPC150, HLA-DQ-a, and XPB. Of these, cyclin B, NPM3, and COL3A1 were higher in DLBCL. Six genes showed statistically significant higher expression in the neoplastic nodes compared with reactive nodes, namely PRKCB1, BCL-6, EAR2, ZFX, cyclin B, YY1. High levels of YY.1 were associated with a shorter survival interval in both FL and DLBCL. The method is simple, sensitive, and robust, facilitating routine use and may be used as a platform for clinical measurement of prognostic gene signatures.

Howard RA, Gilbert ES, Chen BE, et al.
Leukemia following breast cancer: an international population-based study of 376,825 women.
Breast Cancer Res Treat. 2007; 105(3):359-68 [PubMed] Related Publications
PURPOSE: To quantify long-term temporal trends in the excess absolute risk (EAR) of secondary leukemia among breast cancer (BC) survivors, using multivariate analyses to evaluate the effects of subtype, age at BC diagnosis, attained age, and calendar year.
PATIENTS AND METHODS: We identified 376,825 1-year survivors of BC within 4 nationwide, population-based cancer registries in Sweden, Denmark, Finland, and Norway (1943-2001). Estimates of EAR (per 100,000 person-years) were modeled using Poisson regression methods and cumulative risks calculated using a competing risk model.
RESULTS: A total of 687 non-chronic lymphocytic leukemias (EAR = 9.05; 95% confidence interval (CI) = 7.5-10.7) was reported. Significantly elevated risks were observed for the first time for chronic myeloid leukemia (CML) (EAR = 2.06; 95% CI = 1.3-2.9) and acute lymphoblastic leukemia (ALL) (EAR = 0.62; 95% CI = 0.2-1.1), in addition to acute myeloid leukemia (AML) (EAR = 5.00; 95% CI = 3.9-6.2). Excesses of CML, ALL, AML and all leukemias combined persisted over 25 years after BC diagnosis. For all leukemias, EAR decreased with increasing calendar year (P = 0.04) of BC diagnosis. Risk for all leukemia and AML by calendar year of BC diagnosis depended on age at diagnosis. For women diagnosed with BC after 1985, the 10-year cumulative risk of leukemia for those diagnosed before and after age 50 was small, 0.10% and 0.14%, respectively.
CONCLUSIONS: Although secondary leukemia is a rare event, BC survivors experience statistically significant excesses for at least 25 years after diagnosis, including CML and ALL. Decreasing leukemia risks in recent calendar years likely reflect changes in treatment.

Raynaud P, Garrel R, Rigau V, et al.
[How can the diagnostic value of head and neck biopsies be increased in Wegener's granulomatosis: a clinicopathologic study of 49 biopsies in 21 patients].
Ann Pathol. 2005; 25(2):87-93 [PubMed] Related Publications
Head and neck biopsies usually have a low diagnostic value in Wegener's granulomatosis (WG). On the basis of 49 biopsies obtained from 21 WG patients at diagnosis from various sites, i.e. nose (29), paranasal sinus (7), oral cavity (4), larynx (4), conjunctiva (3) and external ear (2), we described the suggestive histological features and studied the diagnostic potential of the biopsy size, anaesthesia method (general (GA) or local (LA)), anatomic region of the biopsy, number of sections, and presenting macroscopic manifestations. Associated granulomatous inflammation (scattered giant cells, 28.5% of biopsies; poorly-formed granulomas, 28.5%), necrosis (neutrophilic microabscesses, 16.3%; geographic necrosis, 18.3%), angiitis (leukocytoclastic, 10%; necrotizing, 12%; and granulomatous, 6%) which confirmed the diagnosis were only present in 18.3% of the biopsies (28.5% of the patients). We think it is possible to propose a "WG-compatible" diagnosis when at least one of these histological features is present (24.5% of biopsies, 26% of patients in our study). We found that it was always better to perform biopsies targeted on macroscopic lesions. When there was no lesion, samples from paranasal sinuses obtained under GA had the highest diagnostic value in the head and neck region, whereas 90% of nasal systematic biopsies performed under LA were nonspecific. Moreover, we demonstrated that performing two further sections increased the sensitivity of histological examination by 7%.

Chen S, Ye J, Kijima I, et al.
Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue.
J Steroid Biochem Mol Biol. 2005; 95(1-5):17-23 [PubMed] Related Publications
By performing primer-specific RT-PCR analyses, three laboratories including ours have found that exons I.3 and PII are the two major exon Is present in aromatase mRNAs isolated from breast tumors. These results suggest that promoters I.3 and II are the major promoters directing aromatase expression in breast tumors. The characterization of transcription factors that interact with the two elements near promoters I.3 and II, i.e., S1 and CREaro, helps us better understand the mechanism of the switch of promoter usage between normal breast tissue and cancer tissue. The positions of the two regulatory regions were mapped by DNase I footprinting and DNA deletion analyses. We applied the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library for genes encoding the proteins binding to these regions. Our results suggest that in normal breast tissue, the function of promoters I.3 and II is suppressed through the binding of EAR-2, COUP-TFI, and RARgamma to S1, and through the binding of Snail/Slug proteins to their binding site that quenches the CREaro activity. In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. In a separate study, we found that estrogen could up-regulate aromatase expression in breast cancer cells by a non-genomic action of ERalpha via cross-talk with growth factor-mediated pathways. Our preliminary results suggest that protein kinase C delta participates in this ERalpha-growth factor mediated regulation. To further understand the regulatory mechanism, we have recently initiated an in vivo footprinting analysis of the -260/+76 bp region of promoter I.3. The experiments were conducted with both MCF-7 and MDA-MB-231 breast cancer cells. Our results revealed several footprinted sites. Five regions (sites 1-5) were then selected for functional analysis through DNA site-directed mutagenesis experiments. This analysis has also confirmed the promoter I.3 TATA site and Snail/Slug binding site. These mutants showed higher luciferase activity when compared to the wild-type, indicating that the proteins binding to these sites were acting as repressors. By reviewing findings from our laboratory and other laboratories, a detailed mechanism for the transcriptional regulation of aromatase expression in breast cancer tissue is summarized and discussed.

Yang C, Yu B, Zhou D, Chen S
Regulation of aromatase promoter activity in human breast tissue by nuclear receptors.
Oncogene. 2002; 21(18):2854-63 [PubMed] Related Publications
Using the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library, we have found that four orphan/nuclear receptors, ERRalpha-1, EAR-2, COUP-TFI (EAR-3), and RARgamma, bind to the silencer (S1) region of the human aromatase gene. S1 down regulates promoters I.3 and II of the human aromatase gene. In this study, the interaction of EAR-2, COUP-TFI, and RARgamma with S1 was confirmed by DNA mobility shift analysis. In contrast to the findings that ERRalpha-1 behaves as a positive regulatory factor, these three nuclear receptors were found, by mammalian cell transfection experiments, to act as negative regulatory factors by binding to S1. Furthermore, the negative action of these three nuclear receptors could override the positive effect of ERRalpha-1. RT-PCR analysis of 11 cell lines and 55 human breast tumor specimens has shown that these nuclear receptors are expressed in human breast tissue. Since EAR-2, COUP-TFI, and RARgamma are expressed at high levels, it is likely that S1 is a negative regulatory element that suppresses aromatase promoters I.3 and II in normal breast tissue. In cancer tissue, S1 may function as a positive element since ERRalpha-1 is expressed, but EAR-2 and RARgamma are only present in a small number of tumor specimens. This hypothesis is sustained by the finding that there is a weak inverse correlation between the expression of COUP-TFI and that of aromatase in breast tumor tissue. Our studies have revealed that estrogen receptor alpha (ERalpha) can also bind to S1, in a ligand-dependent manner. By binding to S1, ERalpha down-regulates the aromatase promoter activity. These results demonstrate that nuclear receptors play important roles in modulating aromatase expression in human breast tissue.

Chen S, Zhou D, Yang C, et al.
Modulation of aromatase expression in human breast tissue.
J Steroid Biochem Mol Biol. 2001; 79(1-5):35-40 [PubMed] Related Publications
Aromatase plays an important role in breast cancer development through its role in the synthesis of estrogen. Aromatase expression in breast tissue can be regulated by several mechanisms. The major promoter usage for aromatase expression in breast tumors (i.e. cAMP-stimulated promoters I.3 and II) is different from that in normal breast tissue (i.e. glucocorticoid-stimulated promoter I.4). Recent characterization of transcription factors that interact with the two important regulatory elements near promoters I.3 and II, i.e. S1 and CREaro, helps us better understand the mechanism of the switch of promoter usage between normal breast tissue and cancer tissue. It is thought that in normal breast tissue, the function of promoters I.3 and II is suppressed through the binding of EAR-2, COUP-TFI, and EARgamma to S1, and through the binding of Snail/Slug proteins to their binding site that quenchs the CREaro activity. In cancer tissue, the expression levels of EAR-2, COUP-TFI, EARgamma, Snail, and Slug decrease, and aromatase expression is then up regulated through the binding of ERRalpha-1 to S1 and the binding of CREB or related factors to CREaro. Results from this and other laboratories reveal that aromatase activity in aromatase expressing cells can also be modified by treatment with aromatase inhibitors and the antiestrogen ICI 182, 780. While aromatase inhibitors are used to treat breast cancer, the treatment has been found to increase the level of aromatase in the breast tissue of some patients. The enhancement of aromatase activity by aromatase inhibitors is thought to be due to a decrease of aromatase protein degradation by enzyme-inhibitor complex formation, up-regulation of the aromatase gene transcription through a cAMP-mediated mechanism, and an induction of aromatase expression by gonadtropins that are released from the pituitary in response to a reduction of estrogen levels in circulation in premenopausal women. Antiestrogen ICI 182, 780 has been found to suppress aromatase expression, but the mechanism has not yet been determined. In addition, aromatase activity and expression can be affected by environmental chemicals. A detailed structure-function study has revealed that flavones, but not isoflavones, are inhibitors of aromatase. It was found that flavones bind to the active site of aromatase in an orientation in which their rings-A and -C mimic rings-D and -C of the androgen substrate. The modulation of aromatase expression by endocrine disrupting chemicals is exemplified by two organochlorine pesticides (i.e. toxaphene and chlordane) that have been found to be antagonists of ERRalpha-1 orphan receptor. These compounds reduce ERRalpha-1 activity, resulting in a suppression of aromatase expression.

Yang C, Zhou D, Chen S
Modulation of aromatase expression in the breast tissue by ERR alpha-1 orphan receptor.
Cancer Res. 1998; 58(24):5695-700 [PubMed] Related Publications
We have previously identified a silencer element (S1) that is situated between promoters I.3 and II of the human aromatase gene and that down-regulates the action of these promoters. We recently applied the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library for genes encoding the proteins binding to the silencer region. Most proteins identified from this approach belong to the nuclear receptor superfamily. Fifty % of the positive clones encode for ERR alpha-1, and other positive clones include EAR-2, EAR-3 (COUP-TF1), RAR gamma, and p120E4F. Because ERR alpha-1 was found to be the major protein interacting with S1, we decided to examine the regulatory action of ERR alpha-1 on promoter I.3 of the human aromatase gene. Using a reporter plasmid that includes the aromatase genomic fragment containing promoter I.3 and S1, ERR alpha-1 was found to have a positive regulatory function in breast cancer SK-BR-3 cells. Gel mobility shift assays have confirmed that ERR alpha-1 binds to S1 in a dose-dependent manner, and DNase I footprinting analysis has revealed that ERR alpha-1 binds to a region, 5'-AAGGTCAGAAAT-3', which is within S1 and between 96 and 107 bp relative to the transcriptional start site of promoter I.3. In addition, despite the fact that the nuclear receptor SF1 was shown previously to bind to the same site and to mediate a cAMP response in ovary, our yeast one-hybrid screening did not find any SF-1 clones. Gel mobility shift assays further revealed that SF-1 can bind to the silencer element with an affinity comparable with ERR alpha-1. Because our reverse transcription-PCR analysis was not able to detect SF1 mRNA in breast cancer tissue or in SK-BR-3 cells, it is thought that SF1 protein is not expressed in breast cancer tissue. Two ERR alpha-1 RNA variants with differences at the 5'-end have been reported. Our reverse transcription-PCR analysis identified the shorter variant in 28 of 32 breast tumor specimens and the longer variant in only 1 specimen. In addition, the shorter variant was detected in breast cancer SK-BR-3 cells as well as in a breast tumor fibroblast line WS3TF. The results suggest that ERR alpha-1 is one of the nuclear proteins interacting with S1 in breast cancer tissue. It is thought that the silencer element in the human aromatase gene may function differently in different tissues because of distinct expression patterns of transcription factors.

Langtry JA, Kirkham P, Martin IC, Fordyce A
Tie-over bolster dressings may not be necessary to secure small full thickness skin grafts.
Dermatol Surg. 1998; 24(12):1350-3 [PubMed] Related Publications
BACKGROUND: The accepted method for securing full thickness skin grafts (FTSG) is with a tie-over bolster dressing, with or without basting sutures. We question the need for tie-over bolster dressings for small FTSGs.
OBJECTIVE: We describe our method of FTSG reconstruction and the outcome in a consecutive series.
METHODS: Thirty patients with surgical defects following tumour excision from the face24, scalp1, ear2, and finger3 ranging in diameter from 8 to 45 mm (mean 20 mm) were reconstructed with a FTSG. Interrupted monofilament nylon perimeter sutures only were used, with antibiotic ointment at the wound edge with either a light dressing or no dressing.
RESULTS: A series of 30 FTSG secured without a tie-over bolster dressing or basting sutures is described, all with good to excellent long term results. In two cases there was early superficial necrosis of the graft, but ultimately 100% graft take.
CONCLUSION: We have found tie-over bolster dressings and basting sutures to be unnecessary in our series of small FTSG. This technique saves time and material and minimizes handling of the graft.

Chu K, Zingg HH
The nuclear orphan receptors COUP-TFII and Ear-2 act as silencers of the human oxytocin gene promoter.
J Mol Endocrinol. 1997; 19(2):163-72 [PubMed] Related Publications
We have previously shown that COUP-TFII and Ear-2, two members of the nuclear orphan receptor family, are able to repress oestrogen-stimulated transcriptional activity of the human oxytocin (OT) gene promoter by binding to a site that overlaps with the oestrogen response element (ERE) present in the 5' flanking region of the gene. Although most nuclear receptor-mediated transcriptional repression conforms with the paradigm of passive repression and involves competitive binding to an activator site, active repression, i.e. silencing of basal promoter activity, has been observed in a limited number of cases. Here we show by co-transfection experiments using COUP-TFII and Ear-2 expression vectors and reporter constructs containing OT gene promoter fragments linked to the chloramphenicol acetyltransferase gene that both COUP-TFII and Ear-2 are capable of silencing basal OT gene promoter activity by 54 and 75% respectively. 5' Deletion and footprint analyses revealed two areas of functionally important interaction sites: (1) a direct TGACC(T/C) repeat overlapping the ERE and (2) a more promoter-proximal area centred at - 90 containing three imperfect direct repeats (R1-R3) spaced by four nucleotides each. Mutagenesis of reporter constructs as well as electrophoretic mobility-shift assays demonstrated that each of the three proximal repeats R1-R3 contributed to orphan receptor binding and the silencing effect. Inasmuch as the orphan receptor-binding sites are not involved in mediating basal transcriptional activity of the OT gene promoter, the observed effects are best interpreted as active repression or promoter silencing. Moreover, since COUP-TFII and Ear-2 are both co-expressed in OT-expressing uterine epithelial cells, the novel transcriptional effects described here are likely to be of functional importance in the fine-tuning of uterine OT gene expression in vivo.

Ioannides C, Fossion E
Reconstruction of extensive defects of the parotid region: experience with the pectoralis major and free latissimus dorsi flaps.
J Craniomaxillofac Surg. 1997; 25(2):57-62 [PubMed] Related Publications
Large defects of the parotid region resulting from excision of malignant tumours, or necrotic tissue due to radiotherapy, should not always be closed with local tissue, for several reasons. Occasionally, myocutaneous flaps are indicated, giving better results. We describe the problems of such tissue defects and our experience over a 10-year period using 2 different flap reconstruction techniques. A total of 28 cases, 25 with malignant tumours of the parotid or the external ear, 2 with extensive radionecrosis of the parotid region and 1 with a burn, were evaluated. The defects were restored with a pectoralis major flap in 21 cases and with a free latissimus dorsi flap in 7 cases. The follow-up ranged from 18 to 60 months. The flaps were successful in achieving stable wound healing, restoration of tissue volume and in helping patients to return to normal life activities. There were complications in 28.5% of the cases. There were 2 early deaths due to encephalitis. Two pectoralis major flaps (9.5%) failed partially. All latissimus dorsi flaps survived. The pectoralis major proved to be useful, especially in older and medically compromised patients, whereas the latissimus dorsi fared well in younger female patients and in cases of a hemifacial resection defect. Numerous technical points in both methods are emphasized.

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