Multistage Progression of Infiltrating Ductal Mammary Adenocarcinoma in Transgenic Mice Expressing SV40 Tag under the Regulatory Control of the Rat Prostatein [C3(1)] Gene

Summary:

Transgenic mice carrying the C3(1)/SV40 Tag fusion gene develop dysplastic lesions in the mammary ductal epithelium beginning at 2 months of age. Lesions quite similar to human ductal carcinoma in situ (DCIS) are observed which progress to infiltrating ductal mammary adenocarcinomas in 100% of the female mice which die by 6-7 months of age. Expression is limited to ductal epithelium and terminal end buds and not to alveolar cells. The C3(1) gene also directs the expression of Tag to the prostate resulting in the development of prostatic intaepithelia neoplasia (PIN) leading to invasive adenocarcinomas in male mice.

Background:

The rat prostatein (C3[1]) gene directs high levels of expression of prostatic steroid binding protein in the rat ventral prostate. This gene is transcriptionally regulated by androgen and multiple hormone receptor elements are contained throughout the 5’ flanking, exon and intron regions of the gene. When 4.5 kb of 5’ flanking region of the C3(1) gene was fused to the early region of SV40, Tag expression was directed to the prostate as well as mammary glands, suggesting that the transcriptional response to steroid hormones was not limited to androgens, but included estrogens and perhaps other hormones as well. In addition, expression to the mammary epithelium may not require estrogen, suggesting that there may be epithelium-specific, hormone-independent, regulatory elements contained within the regulatory region. SV40 expression is limited to the mammary ductal epithelium and terminal end buds. Transgene expression and tumor formation does not require pregnancy or hormone manipulations. Metastases to the lung in the original founder lines is observed in about 10-15% of animals. When crossed into the SV129 background, more than 50% of animals develop metastases.

Citations:

Maroulakou, I. G., Anver, M., Garrett, L. and Green, J. E.: Prostate and breast cancer in transgenic mice carrying a rat C3(1) SV40 TAG fusion gene. Proc. Natl. Acad. Sci. USA 91: 11236-11240, 1994.

Shibata, M.-A., Maroulakou, I. G., Jorcyk, C. L., Gold, L. G., Ward, J. M. and Green, J. E.: p53-independent apoptosis during mammary tumor progression in C3(1)/SV40 large T antigen transgenic mice: suppression of apoptosis during the transition from preneoplasia to carcinoma. Cancer Res. 56: 2998-3003, 1996.

Maroulakou, I., Shibata, M.-A., Jorcyk, C. L., Chen, X-X. and Green, J. E.: Reduced p53 dosage is associated with mammary tumor metastases in C3(1)/TAG transgenic mice. Molecular Carcinogenesis 20: 168-174, 1997

Mammary Phenotype:

Atypical hyperplasias of mammary ductal epithelium are observed at about 8 weeks of age. Lesions progress to nodular atypical hyperplasias at about 14 weeks of age which are similar to ductal carcinoma in situ (DCIS) observed in human mammary cancer. Beginning at about 16 weeks of age, infiltrating ductal adenocarcinomas are observed which histologically resemble human infiltrating ductal mammary adenocarcinoma. 100% of heterozygous females develop mammary adenocarcinomas. Expression of the transgene is not observed in differentiated alveolar cells and mice heterozygous for the transgene are able to lactate. However, mice homozygous for the transgene develop significantly more ductal lesions and are unable to lactate in sufficient quantity to support their offspring. All virgin females develop mammary carcinomas. Pregnancy and/or hormone manipulations are not required for transgene expression or lesion development. We have demonstrated that there is a dramatic rise in apoptosis levels in preneoplastic lesions (>10%) but a significant reduction in apoptosis occurs during the transition to invasive carcinoma. This appears to be a critical event at this stage of tumor progression.

Mammary development:
Alterations in development and during pregnancy are currently being investigated.

Gene Expression:

Expression of genes involved in cell cycle regulation and apoptosis during tumor progression are under investigation.

Mechanistic Implications:

The 5’ flanking region of the rat C3(1) gene is expressed in mammary ductal cells and terminal end buds, not acinar cells. Expression is hormone-responsive, but not hormone dependent, implying that epithelial-specific regulatory elements are contained within the C3(1) gene. Acinar development appears to occur normally in heterozygous but not homozygous mice, which can not support support milk production for their offspring.

Mouse Strain:

FVB/N

D10.B2

Keywords:

C3(1), SV40 Tag, dysplasia, nodular atypical hyperplasia, DCIS, hormone-responsive promotor

infiltrating ductal adenocarcinoma

Contributed by:

Jeffrey E. Green
Head, Transgenic Oncogenesis Group
Laboratory of Cell Regulation and Carcinogenesis
Building 41, Room C629 41 Library Dr.
NIH
Bethesda, MD 20892

Phone: 301-435-5193
Fax: 301-496-8395

        Email: JEGreen@nih.gov