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Precocious Differentiation of the Virgin Wistar-Kyoto Rat Mammary Gland¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Dr. Michael N. Gould, Department of Oncology, K4/334 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792. E-mail: gould{at}humonc.wisc.edu

The Wistar-Kyoto (WKY) rat strain expresses high levels of ß-casein in its virgin mammary glands. We found that the onset of ß-casein overexpression (BCO) occurs at 6 weeks of age, with morphological differentiation of the mammary gland detectable at 7 weeks of age. BCO was previously shown to be cell autonomous; however, we found that adrenal and ovarian hormones were permissive and necessary for the expression of the BCO phenotype, indicating that the genetic variation that initiates BCO from within the mammary epithelium can only manifest BCO in the presence of virgin hormone levels. Sequencing of the WKY and Wistar-Furth (WF) rat ß-casein promoters showed them to be identical. Culture of primary rat mammary epithelial cells (RMEC) under lactogenic conditions revealed that expression of ß-casein was independent of epidermal growth factor (EGF) in RMEC from virgin WKY_v, but was dependent in WF_v, RMEC. RMEC from a pregnant WF_p responded similarly to WKY_v RMEC, suggesting that EGF-independent ß-casein expression occurs naturally in differentiated rat mammary epithelium. However, induction of ß-casein expression in RMEC from immature WKY rats was also independent of EGF, indicating that the induction as well as maintenance of BCO do not require EGF. We suggest that an EGF-independent signaling pathway, arising from a trans-acting inherited effector(s), underlies BCO.

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