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Effect of Estrogen on Progression of Human Proliferative Breast Disease in a Xenograft Model.

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Annual rept. 1 Aug 95-31 Jul 96,

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We have utilized a xenograft model of early human breast cancer progression to identity genetic and cellular changes that occur during breast cancer development and to experimentally manipulate these changes to determine which alterations play a causal role in progression. Alterations in relevant markers, viz., ERDNA methylation status of ER gene and genomic instability were examined to determine if these correlate with progression. Our data show that conformation altered wild type is overexpressed in MCF10AT system cells which is defective in both DNA binding activity and in its ability to function as a transcription factor. We also show that the activated ER gene in MCF10AT system cells is functional based on its ability to mediate E2-regulated increase in transcription from both endogenous and exogenous genes. Transcriptional activation of the endogenous ER gene does not appear to be related to a change in methylation status of the gene. E2 significantly enhanced both the number and size of soft-agar colonies formed by MCF10AT3c cells, a line from a third generation of MCF10AT xenograft lesion. This suggests that xenograft passage has selected for growth regulatory pathways that are E2-responsive and that identification of these pathways and their role in progression will aid in determining how E2 acts to increase risk of breast cancer.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Biology
  • Medicine and Medical Research

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