The role of steroids in neoplastic tissue growth

Laing, Linda M (1980) The role of steroids in neoplastic tissue growth. PhD thesis, University of Glasgow.

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The evaluation of the level of oestrogen receptor protein in the soluble fraction of mammary tumour tissue has been shown to provide an index of response by breast cancer patients to hormonally-based therapeutic regimes. This method, although giving a better indication than physical or clinical features, is not completely reliable, since some tumours do not respond favourably to endocrine manipulation despite containing receptor. It has been of interest, thus, to expand the study of receptor availability as an index of hormonal stimulation by examining the integrity of the hormonal mechanism of action as a whole. In the present study, nuclear as well as cytoplasmic receptor levels have been considered on the basis that entry of receptor into the nucleus and subsequent binding to acceptor sites on chromatin are essential prerequisites of long-term hormonal stimulation. The presence of receptor within the nucleus should thus indicate that the cell's translocation mechanism had survived malignant transformation, and give further evidence of a hormonal component in tissue growth. A defect in translocation would be a major point of blockage in the endocrine system, although further steps may also be sensitive to damage. Using this approach, oestrogen receptor levels have been measured in 1000 mammary tumour biopsies representing both primary and advanced lesions from women of all ages. Using the criterion that only samples containing receptor at both cellular levels are truly hormone-dependent, 33% of tumours were identified as potentially responsive to hormone therapy. Two abnormal situations were discovered where receptor was present in one cellular fraction only. These represented only a small percentage of cases, and appeared to indicate tumour autonomy. Good, but not perfect, continuity was noted in receptor status estimated in primary and secondary or early and late secondary biopsies from the same patient. Receptor content was examined in relation to several variables. Absolute level of both cytosol and nuclear receptor was seen to increase with patient age, but this effect seemed to be menopausally - rather than age - related. Menopause also appeared to influence slightly the distribution of receptors within the cell. Most dramatically, the situation where receptors were present in the nucleus alone was detected in only postmenopausal tissue. No correlation between tissue receptor status and nodal involvement, histological grade, lactalbumin content, plasma steroid levels or plasma receptor content was noted. Follow-up data were collected concerning a number of patients who had received hormonal manipulation as the sole form of treatment at some time subsequent to assessment of receptor status in a tumour biopsy. In 70% of cases where hormonal-dependence was indicated by receptor presence in both soluble and pellet fractions, the patient experienced benefit for at least six months. Only 10% of those patients whose biopsies had contained no detectable receptor responded to any form of hormone therapy, and this was presumably by some indirect pathway. In cases where receptor presence was limited to one fraction, only a small percentage responded. Overall, in 85% of cases the response to hormonal therapy was correctly predicted from receptor status of the biopsy. Further follow-up data revealed that the presence of receptor at both cellular levels indicated a much improved prognosis over complete absence. The disease free interval in cases where receptor had been detected in only one fraction was similar for either fraction and tended towards the pattern displayed by receptor-negative tumours. A comparison was made between the influence of receptor and nodal status on prognosis. Receptor-positive lesions with no nodal infiltration indicated the best prognosis, receptor-negative biopsies displaying nodal involvement giving the worst. In cases of no receptor, but some nodal involvement, or no nodal infiltration, but detectable receptor levels, very similar prognosis was noted initially, with nodal status becoming predominant with time. In the course of designing this assay system, the instability at low temperatures of the hormone/receptor complex from both fractions became apparent. Dissociation of the hormone was accelerated at higher temperatures, but was appreciable at 4

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Robin Leake
Keywords: Oncology, Endocrinology
Date of Award: 1980
Depositing User: Enlighten Team
Unique ID: glathesis:1980-72397
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 May 2019 15:12
Last Modified: 24 May 2019 15:12

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