A study of the relationship of apoptosis and proliferation to local recurrence in breast cancer

Daniel, Syble P. S. (1999) A study of the relationship of apoptosis and proliferation to local recurrence in breast cancer. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (22MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

This retrospective study on breast cancer investigated the inter-relation of the apoptotic factors, Bcl-2, Bax, and proliferation factors Ki-67, PCNA, together with their potential as predictors of local recurrence of tumour. Tumour specimens of patients with local recurrence (defined as recurrence of tumour within a period of 5 years following diagnosis, at the site of original surgery or adjacent axillary region) were expected to show increased proliferation and decreased apoptotic behavior thereby substantially increasing the risk of local recurrence. In addition, loss of function of the tumour suppressor gene, p53, which normally functions as the inhibitor of the proliferation and an activator of the apoptosis, was expected to play an integral part in promoting tumour growth. -- Immunohistochemical analysis of the apoptotic and proliferative markers showed several significant associations between the biological parameters. Analysis of the association between p53 and Bcl-2 expression indicated no statistical significance. Further analysis of the raw data revealed a general trend towards an inverse association between the two markers. Thus, suggesting that p53 in its mutant form behaves in a similar manner as the wild type p53 which functions to inhibit the expression of Bcl-2. Loss of p53 function was also associated with an increase in the proliferative rate as measured by the expression of Ki-67 and PCNA. -- The Bcl-2 protein, known to inhibit apoptosis, failed to display an inverse association with the rate of apoptosis (as measured by the TUNEL method) and the pro-apoptotic protein, Bax. In addition, Bcl-2, also known to promote the retention of cells in the G0/G1 phase of the cell cycle did not exhibit an inverse relationship with expression of Bcl-2 expression and the proliferative markers, Ki-67 and PCNA. -- Among the clinicopathological parameters such as tumour grade and lymph node status, only tumour size showed a significant association with local recurrence where tumour size greater than 2 cm indicated an increased likelihood of local recurrence. In an analysis of the inter-relation between the biological parameters and clinicopathological features, tumour grade and not tumour size exhibited significant positive associations with Bcl-2 and p53 expression. As expected, Bcl-2 positive tumours were associated with low tumour grade while loss of p53 function was associated with high tumour grade. The presence of lymph node status indicated a positive association with the proliferative marker, PCNA. -- Contrary to our expectations, the expression of Bcl-2 and p53 failed to predict local recurrence of breast cancer. The results obtained from the study confirm the need for further analysis of the inter-relations of the biological markers using more quantitative laboratory techniques namely, quantitative RT-PCR and flow cytometry.

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