Analysis of tissue- and hormone-specific regulation of the human prolactin-inducible protein/gross cystic disease fluid protein-15 gene in transgenic mice

Abstract

The human prolactin-inducible protein/gross cystic disease fluid protein-15 (PIP/GCDFP-15) gene is expressed in more than 90% of human breast 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 regulated by a number of hormones including androgen and prolactin. It is not known whether gene expression in normal tissues is under similar hormonal control. To understand the mechanisms by which hormone-and tissue-specific expression of the human PIP/GCDFP-15 gene are regulated in vivo, we generated transgenic mice using a 13·7 kb genomic DNA fragment containing the entire 7 kb human gene, together with 2·9 kilobases of 5 and 3·8 kilobases of 3 flanking sequences. The human PIP/GCDFP-15 transgene was found to be expressed in both the lacrimal and salivary glands but was not expressed in the mammary glands of transgenic mice. This tissue-specific pattern of the transgene expression in the 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 less in the submaxillary (submandibular) and absent in the sublingual glands. In the mouse lacrimal gland, as in the human breast cancer cell lines, the human PIP/GCDFP-15 transgene was also up-regulated by androgen. These studies demonstrate that the human gene with its 6·3 kb flanking sequences is able to confer gene expression in vivo in a tissue-specific and hormone-responsive manner.

Identification of bovine prolactin in seminal fluid, and expression and localization of the prolactin receptor and prolactin-inducible protein in the testis and epididymis of bulls exposed to ergot alkaloids

“…These data would indicate that PIP expression in the testis and epididymis is not heavily regulated by PRL (or ergot alkaloids). This is in contrast to breast cancer cells in which PRL and/or androgens stimulate PIP expression [44,45]. However, PIP is not expressed in normal breast tissue and little has been documented about the regulation of its expression in glands in which the protein is normally produced.…”

Altered Distribution of Aquaporin 5 and its C-Terminal Binding Protein in the Lacrimal Glands of a Mouse Model for Sjögren's Syndrome

“…23 In murine LGs, the human PIP transgene is reportedly up-regulated by androgen. 34 The synthesis of the lacrimal gland MUPs was regulated by testosterone. 35 SS occurs exclusively in women, and this gender difference is related to the androgen deficiency response in human LGs.…”

Significance, detection and markers of disseminated breast cancer cells

“…It is a small protein that is considered as a highly specific and sensitive marker of apocrine differentiation (Jones et al 2001). It has been identified in most breast cancer biopsies (Myal et al 1998, Clark et al 1999, in correlation with steroid receptor status. In agreement, androgens, oestrogens and glucocorticoids have been found to regulate PIP expression (Murphy et al 1987).…”