Characterization of molecular events in the pathogenesis and development of breast cancer

Breast cancer may arise from a progressive accumulation of genetic alterations. The complete spectrum of these and the stages at which they occur is not known. Epidemiological evidence links mammary epithelial hyperplasias and carcinoma in-situ (so called “early lesions”) with invasive breast cancer. However, whether these lesions represent direct precursors or are merely markers of increased risk is unclear. This thesis is based on the hypothesis that the characterization of the mutational status of genes, such as p53, and loss of heterozygosity (LOH) status of chromosomal regions, in normal tissue, pre-malignant lesions, pre-invasive and invasive breast cancer will yield novel insights into the molecular etiology of breast tumorigenesis.; A LOH study of the chromosomal region 11q23 in axillary lymph node-negative (ANN) breast cancers found that loss at this location was associated with a higher rate of estrogen receptor (ER) positivity. The onset of LOH in “early lesions” surrounding invasive breast cancer was found to be variable between loci, between cases and within cases. Study of a group of synchronous primary breast cancers revealed a markedly lower rate of LOH when compared to a group of solitary ANN tumours.; Study of the tumour suppressor gene p53 showed that when a mutation was present in an invasive breast cancer the same mutation could also be found in all surrounding areas of DCIS but not in any areas of epithelial hyperplasia or normal breast tissue. The spectrum of mutations that could be recognized by a widely used anti-p53 antibody (DO7 clone, Novocastra) was characterized. This knowledge was used to screen a panel of new DCIS cases by immunohistochemistry prior to mutational analysis, aiding detection of p53 mutations in DCIS not associated with invasive disease.; Patterns of LOH in early lesions and synchronous primary tumours is suggestive of an overlapping field effect leading to an heirarchical distribution of genetic alterations with p53 mutation occurring prior to the onset of invasion. Further characterization of these fields could provide improved patient assessment and management. Knowledge of the early genetic steps in breast cancer tumourigenesis may result in new approaches to diagnosis and disease prevention.