Title

Genetic and epigenetic abnormalities in the development and progression of sporadic breast cancer

Date of Completion

January 1999

Keywords

Biology, Molecular|Biology, Genetics|Health Sciences, Pathology|Health Sciences, Oncology

Degree

Ph.D.

Abstract

Molecular genetics has uncovered a set of gene alterations associated with the pathogenesis of sporadic breast cancer. These genes normally control growth/apoptotic mechanisms in breast epithelia. Gene expression of breast epithelia relies on signals permeating a tissue matrix, the centers of which are the proteinaceous nuclear matrices housing the genomes. Selective alteration of growth/apoptotic regulatory genes is viewed in this study in the context of this tissue-specific nuclear matrix which configures and regulates genomic functions. It is hypothesized that a correlation exists between expression of specific nuclear matrix proteins and genetic alterations to hallmark growth/apoptotic regulatory genes in sporadic breast cancer. To evaluate this hypothesis, the following specific aims were addressed: (1) Evaluation of 105 cases of sporadic breast cancer for expression of a tumor-specific nuclear matrix protein; (2) and (3) Assessment of the presence of a hallmark oncogene and tumor suppressor gene in sporadic breast cancer, amplified HER2 and mutated p53; (4) Correlation of nuclear matrix protein expression data with the hallmark sporadic breast cancer genotypic data. Nuclear matrix protein analysis was accomplished through immunohistochemical detection of NM200.4, a nuclear matrix protein found to be overexpressed in breast carcinoma. HER2 amplification was assessed by a non-competitive differential polymerase chain reaction assay, and p53 mutations were detected by heteroduplex analysis and gene sequencing. Tests for correlation were fulfilled using chi-square based analyses such as Pearson's chisquare, the phi coefficient, and the Goodman and Kruskal tau. Complete data was obtained for 88 cases. The mammary tumors contained 70% nuclear matrix protein NM200.4 overexpression, 25% HER2 gene amplification, and 20% p53 gene mutations. Although NM200.4 expression did not show association with the two chosen breast cancer genes at the 95% confidence level, varying confidence levels are observed including high confidence levels with HER2 and the combination of HER2 or p53 gene alterations. Furthermore, HER2 connection appeared to favor estrogen receptor positive and lymph node negative cases, while p53 connection was stronger in estrogen receptor negative and lymph node positive cases. It is concluded that specific nuclear matrix proteins expressed in breast epithelia interact differently with different potential oncogenes or tumor suppressor genes. ^