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Clinical translation of progress in molecular endocrinology

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There has been substantial recent progress in our understanding of the molecular mechanism of oestrogen action, most particularly by the discovery of (i) a second ER (ii) the role of co-repressors/co-activators (iii) the importance of conformational change of ER. This has provided insight into the mode of action of hormonal drugs for breast cancer, and prompted new ideas about potential resistance mechanisms, new strategies for treatment and prevention, and the development of new drugs. Differential conformational change of ER by SERMs seems to determine the specific binding of the receptor to particular co-activators/co-repressors of gene transcription. Perturbation of this molecular system can provide cells resistant to tamoxifen through an increased agonist response. There are clinical data to support an increased agonist response of tamoxifen as a resistance mechanism in breast cancer, but there are few clinical laboratory data to support aberrant co-activator/co-repressor expression as an important mechanism. Recent in vitro studies indicate that MCF7 cells may become resistant to oestrogen deprivation by acquired hypersensitivity to oestrogen. There are clinical data to support this mechanism, and new clinical trials have been designed to determine whether this phenomenon can be utilised in sequential therapy. To achieve optimal clinical exploitation of the progress in molecular endocrinology, there is a need for novel clinical trial design, which will utilise imaging and molecular pathological techniques for assessing the molecular response of tissues. Neoadjuvant treatment of breast cancer offers unique advantages for such studies. Treatment-induced changes in proliferation are a useful intermediate endpoint for the evaluation of molecular relationships in breast carcinomas in vivo and for the assessment of drugs effecting these relationships.

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Dowsett, M. Clinical translation of progress in molecular endocrinology. Breast Cancer Res 2 (Suppl 1), S.12 (2000).

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