TGF‐β promotes cell death and suppresses lactation during the second stage of mammary involution

Transforming growth factor beta (TGF‐β) ligands are known to regulate virgin mammary development and contribute to initiation of post‐lactation involution. However, the role for TGF‐β during the second phase of mammary involution has not been addressed. Previously, we have used an MMTV‐Cre transgene to delete exon 2 from the Tgfbr2 gene in mammary epithelium, however we observed a gradual loss of TβRII deficient epithelial cells that precluded an accurate study of the role for TGF‐β signaling during involution timepoints. Therefore, in order to determine the role for TGF‐β during the second phase of mammary involution we have now targeted TβRII ablation within mammary epithelium using the WAP‐Cre transgene TβRII^(WKO)Rosa26R]. Our results demonstrated that TGF‐β regulates commitment to cell death during the second phase of mammary involution. Importantly, at day 3 of mammary involution the Na–Pi type IIb co‐transporter (Npt2b), a selective marker for active lactation in luminal lobular alveolar epithelium, was completely silenced in the WAP‐Cre control and TβRII^(WKO)Rosa26R tissues. However, by day 7 of involution the TβRII^(WKO)Rosa26R tissues had distended lobular alveoli and regained a robust Npt2b signal that was detected at the apical luminal surface. The Npt2b abundance and localization positively correlated with elevated WAP mRNA expression, suggesting that the distended alveoli were the result of an active lactation program rather than residual milk protein and lipid accumulation. In summary, the results suggest that an epithelial cell response to TGF‐β signaling regulates commitment to cell death and suppression of lactation during the second phase of mammary involution. J. Cell. Physiol. 219: 57–68, 2009. © 2008 Wiley‐Liss, Inc.