Targeted Expression of des(1-3) Human Insulin-Like Growth Factor I (IGF-I) in Transgenic Mice Influences Mammary Gland Development and IGF-Binding Protein Expression

Summary
Transgenic mice carrying the WAP-DES transgene display abnormal involution of the mammary epithelium following the first lactation. About 30 to 50 % of these mice develope abnormal ductal hyperplasia after multiple lactations. This hyperplasia is coupled with loss of secretory lobule and failure to lactate.

Background
A 3 kb rat WAP transgene containing only 949 bp or 5' and 7 bp of 3' flanking DNA directs high levels of copy-number dependent expression to the mammary gland from mid-pregnancy through lactation. The gene is transcriptionally regulated through glucocorticoid and prolactin responsive elements contained within a DNAase I hypersensitive site found at the distal end of the promoter. Copy number dependent expression also requires the 3' untranslated region. In an attempt to preserved the efficient expression observed with the rat WAP transgene, the WAP-DES transgene was constructed using exon replacment. The resulting transgene, however, did not show copy-number dependence. The reason for this is unclear but may be related to either the need for cis-elements contained within the WAP exons, or to a negative feedback effect of the IGF-I on transgene expression. The expression of WAP-DES is found in mammary gland and salivary gland. While the expression in salivary gland has no apparent effect, the expression in mammary gland alters the secretion of IGF binding proteins in milk and the morphology of the mammary gland.

Note: Transgenic mice have been produced that express des(1-3) human IGFI in mammary tissue (info).

Transgene
0.95 kb of the 5' flanking sequence of the rat WAP (-949/+33) gene fused to a hybrid genomic fragment in which the rat WAP exons 1 through 4 were replaced with PCR fragments containing codons 1-21, 22-68, 68-133, and 133-153 of the IGF-Ia cDNA, respectively. The rat WAP 3' untranlated region along with 70 bp of flanking DNA were are fused to codon 153 in the hybyid fragment. Expression occurs in the mammary gland and salivary glands.

mouse strain
B6C3F1xICR

Mammary phenotype

Delayed involution following the first lactation. 30 to 50 % of heterozygous females develop mammary ductile hypertrophy coupled with reduced secretory lobules after two or more lactations. These are incapable of lactation. About 30 % of these females develop adenocarcinomas at 1.5 to 2 years of age and after multiple lactations.

Mammary development
The mechanisms underlying the alterations in mammary development are currently being investigated.

Gene expression
Effects of the transgene on mammary gene expression during lactation is currently being investigated.

Mechanistic implications
The ability to inhibit normal involution coupled with the accumulation of collagen observed after multiple lactations supports the idea that IGF-I may be acting through modulation of the expression of matrix metalloproteinases or their inhibitors.

key words
C3(1), des(1-3)hIGF-I dysplasia, mammary involution

Submitted
by Darryl L. Hadsell on December 20, 1995

Department of Pediatrics
CNRC
Room 10,072
1100 Bates St
Houston TX 77030

Phone: 713-798-7043
Fax: 713-798-7057

Contact for further information
Darryl L. Hadsell (e-mail: dhadsell@mbcr.bcm.tmc.edu)