GENE AMPLIFICATION IN HUMAN BREAST TUMORIGENESIS

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DESCRIPTION (Adapted from the Investigator's Abstract): Gene amplification is one of the most pervasive forms of genetic abnormality occurring in human breast cancers. Detection of this abnormality in cancer cells has, however, mostly been limited to those segments of the chromosomes from which cloned probes for the amplified genes were already available. Recent application of chromosome microdissection and comparative genomic hybridization (CGH) techniques have led to the identification of novel amplified chromosomal segments (amplicons) in breast cancer cells even in the absence of any prior knowledge about the genes amplified on these segments. Additionally, microdissection mediated isolation of DNA from amplification implicating cytogenetic structures (homogeneously stained regions and double minute chromosomes) have also provide us with anonymous amplified chromosome region specific probes helpful in physical mapping of the amplicons seen in tumor cells. These studies have revealed chromosome 20q13 as a novel amplicon in about 18% of primary breast tumors showing strong association with aggressive tumor phenotypes. The broad long term objective of this proposal is to isolate commonly amplified and over-expressed genes encoded on the novel amplicon and evaluate their significance in the development of human breast cancer. The specific aims are: 1) to determine the minimum common region of amplification spanning the newly identified 20q13 amplicon in primary tumors; 2) to isolate the over-expressed genes encoded in the common region of 20q13 amplicon; and 3) to evaluate the significance of these over-expressed genes in the context of tumor tissue phenotypes.