The long term objective of this project is to understand the regulation of mouse mammary tumor virus (MMTV) expression in normal mammary epithelium and how this control translates into the increased incidence of mammary tumorigenesis in nonpregnant, non-lactating parous mice vs. virgin mice. Until now MMTV expression has been best characterized in tumor or transformed cell lines. Unfortunately, there exists discrepancies between the results from these studies and those performed in normal mammary epithelium with respect to both the induction kinetics and hormonal requirements. Because the earlier studies involving normal mammary epithelium are both few and also employ indirect assays, it is the purpose of this project to re- evaluate and extend these investigations using DNA excess hybrization to measure MMTV RNA and radioimmunoassays to measure MMTV peptides. the working hypothesis is derived from a model originally proposed by others: MMTV expression is tightly controlled in virgins and is evoked during pregnancy by elevated hormone levels; this expression then alters the mammary epithelium so that MMTV expression can either continue after pregnancy or, at least, be more readily inducible. The final result is that MMTV expression is less rigidly regulated in parous vs. virgin mice. In particular, it is predicted that MMTV expression in mammary epithelium from parous mice will not require DNA synthesis prior to expression (DNA synthesis is required in tissues from virgins), will require fewer hormones or lesser concentrations of hormones and will be more sensitive to other MMTV inducers and/or less susceptible to MMTV inhibitors than in tissues from virgins. These experiments will be carried out in mammary explant culture in serum-free medium. This project is related to biomedical research in several ways: 1) it will provide more relevant information on the control of MMTV expression in the normal mouse mammary gland, and 2) it may provide insights into the etiology of at least some human breast cancers; which have recently been shown to contain MMTV-like sequences.
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