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Cloning and Characterization of Overexpressed Genes in the Mammary Gland of Rat Strains Carrying the Mammary Carcinoma Suppressor (Mcs) Gene¹

Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin 53792

² To whom requests for reprints should be addressed.

Inbred rat strains vary in their susceptibilities to mammary carcinogenesis. The Copenhagen (COP) and Wistar-Kyoto (WKY) rats are tumor resistant, whereas the Wistar-Furth (WF), Fischer (F344), and outbred Sprague-Dawley (SD) rats are susceptible. A dominant pattern of inheritance acting via the mammary carcinoma suppressor (Mcs) gene(s), which is mainly responsible for mammary tumor resistance, has been defined in the COP and WKY rats. In order to understand the basis of the phenotype, COP and WF mammary mRNAs were used for subtractive hybridization to isolate genes associated with the activity of the Mcs gene(s). Three genes, -casein, lipoprotein lipase, and an unidentified gene, were found to be overexpressed in the mammary gland of the COP rat. In addition to a-casein overexpression, Northern analysis demonstrated that β- and -casein genes were also highly expressed in the mammary glands of tumor-resistant WKY and COP virgin rats but not the susceptible F344, WF, and SD strains. The association of casein gene expression with the tumor-resistant phenotype was further investigated by determining the functional site of the strain-specific casein gene regulation by using a mammary cell transplantation assay. In contrast to its normal endocrine control during pregnancy and lactation, casein gene overexpression was found to be controlled within the mammary epithelial cells of virgin rats. This is also the site of production and action of the Mcs gene product. Comparison of polymerase chain reaction-amplified β-casein precursor RNA levels with the use of reverse transcription-polymerase chain reaction revealed that the regulation of this gene is likely at the transcriptional level. These data suggest an association of overexpression of casein genes, with the Mcs phenotype. The biological significance of this association is under investigation.

¹ Supported by a grant from the USPHS, NIH Grant CA28954.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/24/93. Accepted 9/22/93.

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