Coker, Babatunde Julian; (1998) The expression of p53 and related proteins in human breast tumours and malignant melanomas. Masters thesis (M.S), UCL (University College London).

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Abstract

Individuals with the Li-Fraumeni syndrome possess germline mutations in the p53 tumour suppressor gene. These individuals develop tumours at an early age and in various combinations. One combination is breast cancer and malignant melanoma. Anecdotal reports exist of a greater than expected number of melanomas in patients with sporadic breast cancer and although an association between both tumours has previously been proposed there has been no established molecular, or genetic link. The breast like the skin is developed predominantly from ectoderm and an oestrogenic environment favours the development of both tumours. In fact it has been proposed that the breast is a modified sebaceous gland. Breast cancer is defined on the basis of epidemiological, cytological and pathological lines, but no single classification reliably predicts clinical behaviour in any subset of tumours with a reliability which exceeds 50%. Similarly, prognosis in melanomas is reliably predicted by the best known Breslow's thickness measurement and Clark's levels of invasion respectively, but a subset of tumours of relatively good prognosis induce early metastasis and death. Both tumours have a poorer prognosis in males. Are there detectable similar molecular phenotypic differences in breast tumour and melanoma groups related to distinct clinical behaviour and pathological characteristics? Is there a link between sporadic breast cancer and malignant melanoma, or are there major similarities in the molecular behaviour of both tumours based on a defect in the p53 tumour suppressor gene's control of the cell cycle? The presence of the dysplastic naevus syndrome a.k.a. the atypical mole syndrome increases the risk of the development of melanoma, but the association with breast cancer, although reported has not been established. Is there a link between both conditions based on a defect in the p53 tumour suppressor gene? Sporadic breast cancer afflicts 1 in 12 women in the United Kingdom and malignant melanomas affect a young population at their prime, yet we have been unable to significantly alter the treatment outcomes for these tumours. Have we adopted a simplistic approach to their management? Should we now examine the immunohistochemical anomalies present in these tumours before we offer treatment advice? Aim: (i) To examine the immunohistochemical expression of a set of p53 related oncogenic markers in groups of with patients both breast cancer and malignant melanoma, or breast cancer and the dysplastic naevus syndrome and compare them with control groups of sporadic breast tumours (benign and malignant) of established clinical outcome. Conclusion: The overexpression of p53 in all breast tumours in patients with melanomas suggests that these tumours may harbour mutations (either germline or somatic) in the p53 gene but this can only be confirmed by sequencing the p53 gene. Clinical outcome of the distinct unrelated groups of breast tumours may be related to undetected molecular alterations which may modify, both the prognosis and the response to chemotherapeutic interventions. p53 expression in patients with TiNO tumours may be helpful in predicting early recurrence. Aim: (ii) To examine the expression of p53 protein MIB-1, Bcl-2 and the antimelanoma antibody, HMB-45 in a subset of melanomas in patients with p53 positive malignant breast tumours (n = 9) and compare them with a control group of 66 melanomas F = 46, M = 20. Conclusion: p53 expression in sporadic melanomas is commoner in individuals who also express the protein in the dermo-epidermal junction. The MIB-1 score in the dermo-epidermal junction and Bcl-2 expression in malignant melanomas may be of prognostic significance and suggests an underlying defect in the apoptotic pathways in these tumours. (Abstract shortened.)

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