Precocious Differentiation of the Virgin Wistar-Kyoto Rat Mammary Gland

Abstract The Wistar-Kyoto (WKY) rat strain expresses high levels of β-casein in its virgin mammary glands. We found that the onset of β-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 β-casein promoters showed them to be identical. Culture of primary rat mammary epithelial cells (RMEC) under lactogenic conditions revealed that expression of β-casein was independent of epidermal growth factor (EGF) in RMEC from virgin WKYv, but was dependent in WFv, RMEC. RMEC from a pregnant WFp responded similarly to WKYv RMEC, suggesting that EGF-independent β-casein expression occurs naturally in differentiated rat mammary epithelium. However, induction ofβ -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.