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Phenotypic and Genomic Alterations in Epithelial Atypia and In Situ Breast Neoplasia
Cure of invasive breast cancer is uncertain, and is associated with significant toxicity, both clinically and psychologically. Progression from in situ to invasive cancer is a relatively late event in breast tumor evolution, with earlier lesions already having undergone clonal transformation and genomic instability. Understanding the earliest events in preinvasive breast cancer may allow us to shift the emphasis from cure to prevention. Early breast neoplasia is characterized by a clonal proliferation of epithelial cells, identified histologically as ductal carcinoma in situ (DCIS), and perhaps as earlier forms of atypical ductal hyperplasia (ADH) and flat epithelial atypia. These lesions are presumably derived from even earlier precursor proliferations seen as usual ductal epithelial hyperplasia (UDH). We hypothesize that the earliest epithelial growth is hormonally driven, showing epigenetically controlled changes in protein expression, while the transition to clonal neoplasia represented by atypical and in situ lesions is driven by genomic alteration. We will test this hypothesis by 1) defining the range of phenotypic, epigenetic and genomic alterations in a series of pure UDH, ADH, and DCIS; and 2) comparing the alterations in breast lesions showing synchronous presentation suggestive of a precursor-product relationships: UDH vs. ADH, or ADH vs. DCIS. We will use immunohistochemistry to define protein expression patterns, multiplexed PCR-based analysis of methylation patterns to define epigenetic alterations, and array-based comparative genomic hybridization to define genomic copy number changes. Understanding the evolution of breast neoplasia from non-clonal to clonal growth may allow the future development of prevention strategies to control non-clonal growth and to attack the point of transition to breast epithelial neoplasia. Prevention of breast neoplasia, or reduction in the progression to invasive disease, will have an enormous impact on the morbidity and mortality of breast cancer.
Breast cancer is usually diagnosed when it has progressed to invasive disease. Cure is difficult because of the likelihood of metastatic spread to distant sites. Treatment is associated with both clinical and psychological toxicity. The goal of this proposal is to better understand the earliest phases of breast cancer development so that we can focus on prevention of early disease rather than being limited to attempting cure of late stage disease. Invasive breast cancer actually represents a relatively late stage of disease, since the tumor cell population has existed for many years before it is diagnosed by mammography, or detected as a breast mass. We hypothesize that the earliest breast epithelial cell abnormalities are due to abnormal responses to hormonal stimulation, and are still reversible. However, as the DNA is damaged and a single population of cells emerges, the cell growth becomes neoplastic with potential to progress to invasive disease. Lesions have been identified in “benign” biopsies which show histologic patterns suggestive of cancer. We propose to characterize these abnormal patterns using techniques of immunohistochemistry, detection of DNA methylation, and chip-based tumor DNA copy number analyses to define at what point in tumor evolution such changes occur. We will characterize these changes in individual lesions which are thought to represent preinvasive breast cancer (flat epithelial atypia, atypical ductal hyperplasia, DCIS), and those which are thought to be only reactive (usual ductal hyperplasia). Identification of the exact point in neoplastic progression which tumors take on characteristics of malignant growth (clonality, genomic instability), and identification of the earliest changes in these lesions, may allow the development of new prevention strategies, having an enormous impact on the morbidity and mortality of breast cancer.