Eddie Myers

Associations and Interactions between Ets-1 and Ets-2 and Coregulatory Proteins, SRC-1, AIB1, and NCoR in Breast Cancer

Purpose: Associations between p160 coactivator proteins and the development of resistance to endocrine treatment have been described. We hypothesized that nuclear receptor coregulatory proteins may interact with nonsteroid receptors. We investigated the mitogen-activated protein kinase–activated transcription factors, Ets, as possible interaction proteins for the coactivators SRC-1 and AIB1 and the corepressor NCoR in human breast cancer. Experimental Design: Expression and coexpression of Ets and the coregulatory proteins was investigated using immunohistochemistry and immunofluorescence in a cohort of breast tumor patients (N = 134). Protein expression, protein-DNA interactions and protein-protein interactions were assessed using Western blot, electromobility shift, and coimmunoprecipitation analysis, respectively. Results: Ets-1 and Ets-2 associated with reduced disease-free survival (P < 0.0292, P < 0.0001, respectively), whereas NCoR was a positive prognostic indicator (P < 0.0297). Up-regulation of Ets-1 protein expression in cell cultures derived from patient tumors in the presence of growth factors associated with tumor grade (P < 0.0013; n = 28). In primary breast tumor cell cultures and in the SKBR3 breast cell line, growth factors induced interaction between Ets and their DNA response element, induced recruitment of coactivators to the transcription factor-DNA complex, and up-regulated protein expression of HER2. Ets-1 and Ets-2 interacted with the coregulators under basal conditions, and growth factors up-regulated Ets-2 interaction with SRC-1 and AIB1. Coexpression of Ets-2 and SRC-1 significantly associated with the rate of recurrence and HER expression, compared with patients who expressed Ets-2 but not SRC-1 (P < 0.0001 and P < 0.0001, respectively). Conclusions: These data describe associations and interactions between nonsteroid transcription factors and coregulatory proteins in human breast cancer.

Inverse relationship between ER-beta and SRC-1 predicts outcome in endocrine-resistant breast cancer.

The oestrogen receptor (ER) interacts with coactivator proteins to modulate genes central to breast tumour progression. Oestrogen receptor is encoded for by two genes, ER-α and ER-β. Although ER-α has been well characterized, the role of ER-β as a prognostic indicator remains unresolved. To determine isoform-specific expression of ER and coexpression with activator proteins, we examined the expression and localisation of ER-α, ER-β and the coactivator protein steroid receptor coactivator 1 (SRC-1) by immunohistochemistry and immunofluorescence in a cohort of human breast cancer patients (n=150). Relative levels of SRC-1 in primary breast cultures derived from patient tumours in the presence of β-oestradiol and tamoxifen was assessed using Western blotting (n=14). Oestrogen receptor-β protein expression was associated with disease-free survival (DFS) and inversely associated with the expression of HER2 (P=0.0008 and P<0.0001, respectively), whereas SRC-1 was negatively associated with DFS and positively correlated with HER2 (P<0.0001 and P<0.0001, respectively). Steroid receptor coactivator 1 protein expression was regulated in response to β-oestradiol or tamoxifen in 57% of the primary tumour cell cultures. Protein expression of ER-β and SRC-1 was inversely associated (P=0.0001). The association of ER-β protein expression with increased DFS and its inverse relationship with SRC-1 suggests a role for these proteins in predicting outcome in breast cancer.

CA 15-3 is predictive of response and disease recurrence following treatment in locally advanced breast cancer

BackgroundPrimary chemotherapy (PC) is used for down-staging locally advanced breast cancer (LABC). CA 15-3 measures the protein product of the MUC1 gene and is the most widely used serum marker in breast cancer.MethodsWe retrospectively investigated the role of CA 15-3 in conjunction with other clinico-pathological variables as a predictor of response and time to disease recurrence following treatment in LABC. Pre and post primary chemotherapy serum concentrations of CA 15-3 together with other variables were reviewed and related to four outcomes following primary chemotherapy (clinical response, pathological response, time to recurrence and time to progression). Persistently elevated CA 15-3 after PC was considered as consecutively high levels above the cut off point during and after PC.Results73 patients were included in this study. Patients received PC (AC or AC-T regimen) for locally advanced breast cancer. 54 patients underwent surgery. The median follow up was 790 days. Patients with high concentrations of CA 15-3 before PC treatment had a poor clinical (p = 0.013) and pathological (p = 0.044) response. Together with Her-2/neu expression (p = 0.009) and tumour lympho-vascular space invasion (LVI) (p = 0.001), a persistently elevated CA 15-3 post PC (p = 0.007) was an independent predictive factor of recurrence following treatment in LABC.ConclusionElevated CA 15-3 level is predictive of a poor response to chemotherapy. In addition, persistently elevated CA 15-3 levels post chemotherapy in conjunction with lympho-vascular invasion and HER2 status predict a reduced disease free survival following treatment in locally advanced breast cancer.

The role of oestrogen receptor α in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2

Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.

A positive role for PEA3 in HER2-mediated breast tumour progression.

Overexpression of HER2 is associated with an adverse prognosis in breast cancer. Despite this, the mechanism of its transcriptional regulation remains poorly understood. PEA3, a MAP kinase (MAPK)-activated member of the Ets transcription factor family has been implicated in the transcriptional regulation of HER2. The direction of its modulation remains controversial. We assessed relative levels of PEA3 expression and DNA binding in primary breast cultures derived from patient tumours (n=18) in the presence of an activated MAPK pathway using Western blotting and shift analysis. Expression of PEA3 in breast tumours from patients of known HER2 status (n=107) was examined by immunohistochemistry. In primary breast cancer cell cultures, growth factors induced interaction between PEA3 and its DNA response element. Upregulation of PEA3 expression in the presence of growth factors associated with HER2 positivity and axillary lymph node metastasis (P=0.034 and 0.049, respectively). PEA3 expression in breast cancer tissue associated with reduced disease-free survival (P<0.001), Grade III tumours (P<0.0001) and axillary lymph node metastasis (P=0.026). Co-expression of PEA3 and HER2 significantly associated with rate of recurrence compared to patients who expressed HER2 alone (P=0.0039). These data support a positive role for PEA3 in HER2-mediated oncogenesis in breast cancer.

The impact of evolving management strategies on negative appendicectomy rate

Aim  The management of appendicitis has evolved from the era of open surgery with a negative appendicectomy rate ranging from 20 to 30%. Diagnostic adjuncts such as computed tomography (CT), ultrasound (US) and diagnostic laparoscopy (DL) facilitate refinement of the clinical impression in equivocal cases. The aim of this study was to determine the impact of the increased availability and selective utilization of diagnostic adjuncts on the negative appendicectomy rate.

Incarcerated transmesosigmoid hernia presenting in a 60-year-old man: a case report

IntroductionInternal hernias are a rare cause of small bowel obstruction and are estimated to account for 1% to 5% of cases. Herniation through a defect in the sigmoid mesocolon constitutes 6% of all internal hernias.Case presentationIn this case report we describe a rare case of a fit and healthy 60-year-old man, with no previous history of abdominal surgery, who presented with signs and symptoms of small bowel obstruction as a result of an incarcerated transmesosigmoid hernia. The hernia was reduced and the incarcerated loop of small bowel was found to be viable. The patient made a good recovery and was discharged home on the fourth post-operative day.ConclusionInternal hernias can cause considerable morbidity and mortality, so prompt diagnosis is paramount. Transmesosigmoid hernias are most common in the paediatric population; however, our patient was 60 years old. This report highlights the importance of considering an internal hernia as a cause of small bowel obstruction in individuals of all age groups and especially in those without a previous history of abdominal surgery.

Mesenteric desmoid tumor causing ureteric obstruction

Abstract:  Desmoid tumors are rare, accounting for just 0.03% of all neoplasms and less than 3% of all soft tissue tumors. Although these tumors are benign, they are locally invasive and can cause considerable morbidity and mortality. We describe the case of a 16‐year‐old female who presented with hydronephroureter secondary to an intra‐abdominal desmoid tumor. This case report draws the attention of urologists to the diagnostic dilemma and therapeutic challenges associated with an intra‐abdominal mass causing ureteral obstruction especially in young patients.

The significance of immunohistochemistry positivity in sentinel nodes which are negative on haematoxylin and eosin in breast cancer

INTRODUCTION Sentinel lymph node (SLN) biopsy allows a more detailed examination of a smaller number of lymph nodes in patients with clinically node negative breast cancer. Immunohistochemistry detects small tumour burden not routinely seen on haematoxylin and eosin (H&E). The significance of such findings remains to be fully elucidated. AIM To assess the axillary disease burden of patients in whom the sentinel lymph node biopsy was positive on immunohistochemistry and negative on H and E. METHODS An analysis of patients who underwent SLN mapping for breast cancer at St Vincents University Hospital from January 1st, 2000 to December 31st, 2006 was conducted. All SLNs were assessed by serial H&E and IHC sections. Patients with micrometastases (0.2-2mm) underwent a completion axillary lymph node dissections (CLND). Patients with ITC (<0.2mm) were individually discussed and a CLND was performed selectively based on additional clinicopathological criteria and patient preference. Analysis of the additional nodes from CLND was performed. Patients were followed for a median of 27 months (range 12-72 months). RESULTS 1076 patients who underwent SLN were included for analysis. 211 (20%) had a positive SLN biopsy using H&E. Forty-nine patients (5%) had a negative SLN on H&E which was positive on IHC. Of these, 15 had micrometastases and underwent a CLND. Two had further axillary nodal disease. ITC were found in the remaining 34 patients. Sixteen of these patients underwent a CLND. Five of this group had further nodal disease. CONCLUSION Micrometastases and isolated tumour cells, detected only by immunohistochemical analysis of sentinel lymph nodes, are associated with further positive nodes in the axilla in up to 15% of patients. This upstaging of disease may impact upon patient outcome.

Erratum to: A Predictive Model of Suitability for Minimally Invasive Parathyroid Surgery in the Treatment of Primary Hyperparathyroidism

The online version of the original article can be found underdoi:10.1007/s00268-011-1377-z.D. O. Kavanagh (&) E. Myers R. Kennelly A. D. K. Hill D. Evoy E. W. McDermottDepartment of Breast & Endocrine Surgery,St. Vincents University Hospital, Elm Park, Dublin 4, Irelande-mail: dara_kav@hotmail.comP. FitzpatrickDepartment of Medicine, Physiotherapy & Population Science,School of Public Health Medicine, University College Dublin,Belfield, Dublin 4, IrelandP. FitzpatrickSchool of Medicine & Medical Science,University College Dublin, Belfield, Dublin 4, IrelandS. J. Skehan R. G. GibneyDepartment of Radiology, St. Vincents University Hospital,Elm Park, Dublin 4, Ireland