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Title: CRE MEDIATED GENE DELETION IN THE MAMMARY GLAND.

Author
item WAGNER, KAY-UWE - NIH
item WALL, ROBERT
item ST-ONGE, LUC - MAX-PLANCK INST., GERMANY
item GRUSS, PETER - MAX-PLANCK INST., GERMANY
item WYNSHAW-BORIS, ANTHONY - NIH
item LI, MINGLIN - UNIV OF MARYLAND
item FURTH, PRISCILLA - UNIV OF MARYLAND
item HENNIGHAUSEN, LOTHAR - NIH

Submitted to: Nucleic Acids Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/1997
Publication Date: N/A
Citation: N/A

Interpretive Summary: Several genes have been implicated in mammary gland development and breast cancer. However, in many cases the unequivocal evaluation of these genes in mammary gland function has been impeded because their deletion from the genome results in embryonic lethality or widespread physiological consequences. Therefore, we have developed a transgenic animal system that will allow scientists to delete genes in the mammary gland only after lactation begins. In this study we produced and evaluated transgenic mice containing the Cre recombinase gene. Cre is a protein from bacterial viruses that is capable of cutting out a sequence of DNA that is surrounded by Lox sites, another protein from bacterial viruses. Previously we had generated transgenic mice that carried a gene surrounded by Lox sites. Those animals were used in this study to test our new transgenic mice carrying either MMTV-Cre or WAP-Cre genes. Both MMTV and WAP gene regulatory sequences direct expression of genes to mammary glands. But we found in this study that when MMTV-Cre mice were mated to mice containing Lox sites, the DNA between the Lox sites was cut out in all tissues. Whereas the WAP-Cre x Lox matings resulted in excising DNA between Lox sites only in the mammary gland and only after the mice began to lactate. Therefore we now have a tool that will allow us to specifically target genes in the mammary gland for deletion in order to study their influence on mammary gland function and contribution to the genesis of breast cancer.

Technical Abstract: To delete genes specifically from mammary tissue using the Cre-lox system, we have established transgenic mice expressing Cre recombinase under control of the WAP gene promoter and the MMTV-LTR. Cre activity in these mice was evaluated by three criteria. First, the tissue distribution distribution of Cre mRNA was analyzed. Second, an adenovirus carying a reporter gene was used to determine expression on the level of single cells. Third, tissue specificity of Cre activity was determined in a mouse strain carrying a reporter gene. In adult MMTV-Cre mice the expression of the transgene was confined to striated ductal cells of the salivary gland and mammary epithelial cells in virgin and lactating mice. Expression of WAP-Cre was only detected in alveolar epithelial cells of mammary tissue during lactation. Analysis of transgenic mice carrying both the MMTV-Cre and the reporter transgene revealed recombination in every tissue. In contrast, recombination mediated by Cre under control of WAP gene promoter was largely restricted to the mammary, and occasionally observed in the brain. These results show that transgenic mice with the WAP-Cre but not MMTV-Cre can be used as a powerful tool to study gene function in deelopment and tumorigenesis in the mammary gland.