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Title: The role of steroids in neoplastic tissue growth
Author: Laing, Linda M.
ISNI:       0000 0001 3603 9415
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1980
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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°C over a period of 18 hours. This shows that exchange of added for endogenous steroid can occur at low as well as elevated temperatures, and that this assay system measures both filled and unfilled sites. Thus, it is not possible to distinguish between filled and empty sites by this method. The abnormality of receptors found only in the soluble fraction has been investigated. Preliminary results showed that these receptors could not be induced to translocate into nuclei of a hormone-responsive tissue. This suggests that the defect lies with the receptor rather than cellular functioning in these cases. Receptors were studied in other human tissue types; notably colonic carcinoma. Specific binding was not detected, despite the fact that tentative evidence of hormonal response does exist. An in vitro approach to the study of hormonal dependence was attempted. The isolation procedures and subsequent growth requirements for epithelial cells from mammary tumour biopsies were studied. The most successful method involved the use of a confluent monolayer of non-dividing cells (feeder layer) onto which collagenase-digested tissue was innoculated. In the majority of cases, this enhanced the development of epithelial colonies, while inhibiting stromal cell attachment and growth. Preliminary studies were carried out on the effects of hormones using this system. Initial results suggested that growth on a feeder layer might be a marker of malignancy. However, subsequent findings that "normal" mammary epithelial colonies developed on feeder layer challenged the validity of this marker, and emphasised the requirement for further methods of characterizing cells cultured in this manner.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine