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Biomedical subjects

J R Benson

Publications and source records attributed to J R Benson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Role of TGF beta in the anti-estrogen response/resistance of human breast cancer.

Transforming growth factor beta (TGF beta) has potent inhibitory effects upon epithelial proliferation and malignant progression may be associated with breakdown of the autocrine and paracrine inhibitory loops in which TGF beta participates. The therapeutic effecs of anti-estrogens may be partially attributable to boosting of local endogenous levels of TGF beta. This article reviews the evidence in support of TGF beta being a proximate effector in mediation of the anti-neoplastic effects of anti-estrogens. Both the conventional estrogen receptor (ER) dependent and ER independent mechanisms of action are likely to be involved. Evidence for preferential stromal induction of TGF beta by anti-estrogens is emphasized, together with the therapeutic potential of this strategy for improving outcome in early breast cancer irrespective of ER status.

Autocrine Communication↗
PubMed1996

Localization of impalpable breast lesions--a surgical approach.

The conventional approach to localization of impalpable breast lesions, i.e. employing a hooked wire with either stereotaxis or a perforated plate, has potential disadvantages for the operating surgeon. Often the entry point of the wire lies some distance from the site of projection of the lesion on the skin. The guide-wire should pierce the skin at, or close to, the site of any proposed surgical incision and proceed along the shortest and most direct course towards the lesion. Ideally, the wire should lie within a radial distance of between 1 and 2 cm from its target. A method is described which achieves these objectives and involves both radiological and clinical measurements. A total of 665 guide-wire localized biopsies have been carried out at the above institutions between 1 November 1987 and 31 March 1995 and between 1 January 1994 and 31 March 1996. In only 4% of cases was re-positioning of the wire required. Excision of the radiological lesion was obtained with a single biopsy in 99% of cases. A second or third biopsy was indicated in 0.7% and 0.3% of cases, respectively. Migration of the wire occurred in two patients and no cases of wire transection or pneumothorax were reported. This method of localization facilitates subsequent excision and permits the most appropriate incision consistent with optimal cosmesis.

Breast↗
PubMed1996

Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen.

Tamoxifen may mediate its effect in early breast cancer in part via an oestrogen receptor (ER)-independent pathway by directly stimulating fibroblasts to produce the negative paracrine growth factor transforming growth factor (TGF)-beta. We have previously shown that secretion of this factor is induced 3-to 30-fold in human fetal fibroblasts in vitro, and by stromal fibroblasts in vivo following tamoxifen treatment of ER-positive and ER-negative breast cancer patients. Primary cultures of breast tumour fibroblasts have been exposed to tamoxifen for 48 h, and rates of secretion of TGF-beta 1 and TGF-beta 2 measured using a quantitative immunoassay. Fibroblast strains derived from malignant and benign tumours produced and secreted similar amounts of TGF-beta 1, but benign breast tumour fibroblasts secreted significantly higher levels of TGF-beta 2 compared with fibroblasts of malignant origin. Tamoxifen did not induce any consistent increase in TGF-beta secretion into the conditioned medium, but immunofluorescence analysis for the intracellular form of TGF-beta 1 revealed evidence of increased immunoreactive protein in tamoxifen-treated fibroblasts, which is localised to the nucleus. Therefore synthesis of TGF-beta 1 appears to be stimulated by tamoxifen, but increased secretion may be abrogated in vitro. Furthermore, using immunocytochemistry and transient transfection with an ER-responsive reporter construct, no ER was demonstrable in these fibroblasts supporting the proposed ER-independent paracrine pathway.

Antineoplastic Agents, Hormonal↗
PubMed1995

Microsatellite instability and a TGF beta receptor: clues to a growth control pathway.

Defects of growth inhibitory pathways have an important role in disorders of cell growth and differentiation. The discovery of a mutation in one of the principle components of the transforming growth factor beta (TGF beta) receptor system which is linked to a DNA repair defect(1) represents one possible mechanism of escape from negative regulatory influences acting upon cells. TGF beta is a pre-eminent negative growth factor and this article discusses (1) the role of TGF beta in maintaining epithelial homeostasis; (2) how breakdown of inhibitory pathways can promote neoplastic development; (3) the significance of a receptor defect in a negative signalling pathway; and (4) the potential therapeutic sequelae resulting from restoration of cellular responsiveness to TGF beta.

Animals↗
PubMed1994

Alternative mechanisms of action of anti-oestrogens.

The molecular mechanism of action of anti-oestrogens such as tamoxifen appears to be a complex mixture of antagonism of the mitogenic action of oestradiol at the level of the oestrogen receptor, plus a range of other activities from enzyme inhibition to growth factor modulation. This article will concentrate on two specific areas: 1) the inhibition of protein kinase C and calmodulin-dependent cAMP phosphodiesterase; and 2) the regulation by tamoxifen of peptide regulators of breast cancer epithelial cell growth such as insulin-like growth factor I (IGF I) and transforming growth factor beta (TGF-beta). The elucidation of these mechanisms is potentially important in the treatment and chemoprevention of breast cancer-the quantitative contribution of each individual mechanism of the overall antineoplastic action of anti-oestrogens is central to developing new and possibly more effective anti-oestrogens and optimizing strategies for their use.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Breast cancer, desmoid tumours, and familial adenomatous polyposis--a unifying hypothesis.

There is widespread agreement that epithelial tumours develop as a consequence of primary events within epithelial cells. According to the monoclonal theory, a tumour is caused by genetic change within a single cell, which imparts a selective growth advantage. This simple theory fails to take into account two important concepts. First, tumour generation is likely to involve multiple genetic events, some of which initiate a tumour, and others promote its growth. Second, tumours are usually composed of several tissue components, although they are known by the dominant proliferative cell type. This convention has tended to obscure the importance of "secondary" tissue components in carcinogenesis, despite evidence for the involvement of mesenchymal elements both in the induction and maintenance of transformation. To shift emphasis from the monoclonal theory, we propose a unifying hypothesis accounting for the effect of adjuvant tamoxifen in early breast cancer and the association between gastrointestinal polyps and desmoid tumours.

Adenomatous Polyposis Coli↗