ANALYSIS OF TISSUE-SPECIFIC AND HORMONE-SPECIFIC REGULATION OF THE HUMAN PROLACTIN-INDUCIBLE PROTEIN GROSS CYSTIC-DISEASE FLUID PROTEIN-15 GENE IN TRANSGENIC MICE

The human prolactin-inducible protein/gross cystic disease fluid prote in-15 (PIP/GCDFP-15) gene is expressed in more than 90% of human breas t cancer biopsies but not in the normal mammary gland. However, it is expressed in several normal human apocrine glands such as the lacrimal and salivary glands. In human breast cancer cell lines, the gene is r egulated by a number of hormones including androgen and prolactin. It is not known whether gene expression in normal tissues is under simila r hormonal control. To understand the mechanisms by which hormone- and tissue-specific expression of the human PIP/GCDFP-15 gene are regulat ed in vivo, we generated transgenic mice using a 13.7 kb genomic DNA f ragment containing the entire 7 kb human gene, together with 2.9 kilob ases of 5' and 3.8 kilobases of 3' flanking sequences. The human PIP/G CDFP-15 transgene was found to be expressed in both the lacrimal and s alivary glands but was not expressed in the mammary glands of transgen ic mice. This tissue-specific pattern of the transgene expression in t he mouse was very similar to that of the endogenous human PIP/GCDFP-15 gene, and to the endogenous mouse gene. In the mouse salivary glands, the transgene expression was highest in the parotid, considerably les s in the submaxillary (submandibular) and absent in the sublingual gla nds. In the mouse lacrimal gland, as in the human breast cancer cell l ines, the human PIP/GCDFP-15 transgene was also up-regulated by androg en. These studies demonstrate that the human gene with its 6.3 kb flan king sequences is able to confer gene expression in vivo in a tissue-s pecific and hormone-responsive manner.