E. W. McDermott

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.

COX inhibitors modulate bFGF-induced cell survival in MCF-7 breast cancer cells.

Basic fibroblast growth factor (bFGF) serves as a modulator of survival in breast cancer cells. The mechanisms by which bFGF transduces the anti‐apoptotic signal and interacts with COX inhibitors were investigated. bFGF reduced apoptosis in MCF‐7 breast cancer cells and up‐regulated the expression of mitocondrial Bcl‐2, whereas COX inhibitors meloxicam (selective COX‐2) and aspirin (non‐selective), induced apoptosis. bFGF up‐regulated survivin protein expression and induced cdc‐2 phosphorylation moderately at early (2–6 h), and substantially at late (24 h), time‐points. Survivin mRNA expression was up‐regulated only at the later time‐point. COX inhibitors prevented up‐regulation of survivin protein expression at both 2 and 24 h and prevented early modest increases in cdc‐2 phosphorylation. Up‐regulation of survivin mRNA was not found to be modulated by the COX‐2 inhibitor meloxicam. bFGF regulation of survivin expression was found to be ERK1/2 kinase dependent and bFGF‐induced phosphorylation of c‐raf was prevented by the COX‐2 inhibitor. bFGF was, however, unable to induce COX‐2 protein expression or modulate COX‐2 activity in MCF‐7 cells as evidenced by unaltered PGE2 production. These results indicate that bFGF regulates survivin expression in MCF‐7 breast cancer cells by signaling through an ERK1/2 dependent pathway. COX‐2 inhibitors can modulate bFGF‐induced survivin expression in a COX‐2 independent manner.

Safety guidelines for radiolocalised sentinel node resection

BackgroundSentinel node radiolocalisation procedures are associated with low levels of radiation exposure. Radioactive material is present in the operating theatre and pathology laboratory. In most hospitals there are no official regulations in place for sentinel node radiation exposure.AimTo establish guidelines on the safety of sentinel node mapping with emphasis on the management of radioisotopes.MethodsThe current literature regarding sentinel node procedures and radiation safety was reviewed. EU and US radiation safety regulations were scrutinised.ResultsPersonnel involved in sentinel node procedures are exposed to low levels of radiation. These levels are not high enough to require designated radiation workers in the theatre and pathology laboratory. Awareness of radiation safety and certain precautions during the procedure and processing of the specimen can further reduce levels of exposure.ConclusionAlthough low levels of radiation exposure are associated with sentinel node procedures, awareness of radiation safety and adherence to regulations, along with close interdepartmental co-operation, are recommended for further reduction in radiation exposure and safe application of this technique.

Tamoxifen as the primary treatment in elderly patients with breast cancer.

BackgroundWith the increasing incidence of breast cancer in patients over 70 years, there is interest in the best therapeutic approach.AimsTo review the management of breast cancer in elderly women and to identify the factors involved in the decision to treat patients with tamoxifen as first line therapy.Patients and methodsBetween 1986 and 1999, 302 female patients aged ≥ 70 years presented with primary breast cancer, of whom 219 underwent surgery, 79 received tamoxifen as first line treatment and four received primary radiotherapy. A retrospective review was performed on these 79 patients and the outcome recorded.ResultsOf these 79 patients, data was available on 68. Follow-up ranged from one to 63 months (median 17 months). Co-morbidity was the principal reason for choosing first line tamoxifen therapy in 61% and patient preference in 11%. Tumour size was less than 5cm in 51%. In 25% tumour size decreased, in 24% it remained stable and in 27% it increased in size following tamoxifen therapy. Additional treatment was prescribed for 33% of patients.ConclusionIn the authors’ experience, for those elderly patients suffering considerable co-morbidity or who refuse surgical intervention, tamoxifen is an acceptable alternative.

Value of sentinel node biopsy in the management of breast cancer

AimsTo determine the rate of detection of the sentinel node using both blue dye and radioisotope, and the accuracy with which the sentinel node histology reflects the nodal status of the axilla in a series of patients with clinically node-negative breast cancer.Patients and methodsDuring a 32-month period from May 1998 to December 2000, 73 patients with clinically node-negative breast cancer underwent sentinel node biopsy immediately followed by formal axillary lymphadenectomy. The sentinel node(s) was identified using a combination of lymphoscintigraphy, blue dye and an intraoperative hand-held gamma probe.ResultsThe mean age of the 73 patients was 58 years (range 32–83 years). Twenty-six per cent (19/73) had previous surgical/excisional biopsy. Pre-operative lymphoscintigraphy was positive in 74% (54/73) of patients. Combination of blue dye and radioisotope was better than either method in isolation for identifying the sentinel node, yielding a success rate of 96% (70/73). A total of 32 cases proved to have positive nodal disease on histological examination. In 44% (14/32) of patients, the sentinel node was the only positive node. Forty-seven per cent (15/32) of patients in whom the sentinel node was positive also had positive nodes in the axillary nodal basin. There were 3/32 false negative cases, giving a false negative rate of 9.4%.ConclusionSentinel node biopsy will have a role in the management of breast cancer. However, widespread adaptation of this technique awaits the results of prospective, randomised trials.

Direct pro-angiogenic and indirect pro-metastatic properties of VEGF/VEGF receptors

ConclusionsOur data demonstrate that EC promotes the metastatic potential of cancer cells by enhancing their migratory capability, which is partly due to EC uPA secretion. Two established VEGF receptors; Flt-1 and KDR signal different VEGF-mediated pro-neoplastic activities. Simultaneous blocking of both VEGF receptors allowed VEGF to continue exerting its pro-angiogenic effect. This suggests the possible activation of yet another VEGF receptor undiscovered under these conditions.

Growth factor activation of the mitogen-activated protien (MAP) kinase pathway increases breast coactivator protein expression and stimulates breast tumourigenesis

ConclusionsThese results implicate a growth factor pathway, acting through a MAPK signalling pathway, in the regulation of the coactivator proteins. Alterations in the level of expression or activation of the coactivator proteins alters the delicate balance at the oestrogen receptor and may drive not only tumorigenesis but also the development of endocrine resistance.

Is there an optimal route for injecting radioisotope for sentinel lymph node biopsy injection in patients with breast cancer

ConclusionID injection of radioisotope was associated with a 95% rate of identification of the SLN on lymphoscintigraphy and a 100% identification rate at surgery. We recommend the intradermal route for injecting radioisotope for sentinel lymph node biopsy.

Modulation of coregulatory protein expression in human breast cancer

ConclusionDifferential expression of coregulatory proteins in response to oestrogen receptor modulators may determine the direction of transcription of genes relevant to tumour progression. This shift in equilibrium in the ratio of coactivator to corepressor protein may in part explain resistance to endocrine therapies.

Modulation of c-raf and cdc2 kinase-suryivin expression: role of cyclo-oxygenase inhibitors in breast cancer apoptosis

ConclusionsThese findings suggest aspirin and meloxicam modulate breast cancer cells survival by interfering both cell cycle independent (mitochondrial Bcl-2) and cycle-dependent (survivin) apoptotic pathways. The COX inhibitors efficiently prevented the cdc2-survivin complex activation by reducing the phosphorylation of cdc2 and c-raf. They modulate the anti-apoptotic effect of bFGF independent of COX II activities. The anti-survivin properties of aspirin and meloxicam in our in vitro model may explain the chemoprevention role of COX inhibitors.