Ndisang, Daniel Uche; (1999) The Brn-3 POU domain transcription factors in gynaecological cancers. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Brn-3a and Brn-3b POU factors were originally identified in neuronal cells and neuroblastomas, but their expression in normal cervical and mammary cells has also been reported. As these factors may regulate the expression of genes involved in gynaecological cancers, their pattern of expression and potential role in tumourgenesis was investigated in both breast and cervical neoplastic tissues. The Brn-3 factors have been shown to have antagonistic effects on the transcription of the human papilloma virus types 16 and 18 (HPV-16/18) E6 and E7 oncogenes. Thus, while Brn-3a activates the expression of E6 and E7, Brn-3b represses it. The levels of Brn-3a and Brn-3b were therefore quantified in neoplastic and normal cervical biopsies. Brn-3a was seen to be over-expressed in high grade cervical intraepithelial neoplasia (CIN3) associated with HPV, as compared to normal cervical tissues lacking HPV. This effect was not observed for Brn-3b. To appreciate the role of Brn-3a in cervical neoplasia, its expression in cervical carcinoma-derived cell lines with or without endogenous HPV genes was manipulated. The artificial reduction of Brn-3a, reduces expression of the viral E6 and E7 products. Moreover, morphology, growth rate, saturation density and the anchorage independent proliferation of the cells were altered in the HPV-containing cervical carcinoma cells, but not in similar cells lacking HPV. This indicates that, Brn-3a may play a significant role in HPV-associated cervical cancer. It has also been shown that Brn-3b can repress the promoter of the BRCA-1 tumour suppressor gene. Thus, to Study the role played by Brn-3a and Brn-3b in breast tumourigenesis, the mRNA and protein expression levels of Brn-3a and Brn-3b and that of BRCA-1, in normal, benign and malignant breast tissues were compared. It was found that Brn-3b was over-expressed in a number of breast cancer samples and that these samples also showed reduced expression of BRCA- 1. No correlation was observed between Brn-3a and BRCA-1 expression. The data taken together with the results obtained from recent studies carried out in our laboratory, indicate for the first time that, the Brn-3b transcription factor regulates the expression of BRCA-1 in sporadic breast cancer.

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