Diminished milk fat secretion and premature mammary gland involution in episialin/MUC1 transgenic mice

Background

Episialin (MUC1, EMA, CA15.3) is a membrane-associated mucin and is frequently overexpressed in adenocarcino-mas. If overexpressed, it inhibits cell adhesion, promotes invasiveness, and protects against cytotoxic T-cells in vitro. To study the effects of episialin in vivo, we developed an episialin transgenic mouse model.

Method

Transgenic FVB mice were developed expressing the human episialin gene under the control of the glucocorticoid inducible MMTV promoter. Two transgenic founder lines were selected: one expressing relatively low levels (F64) and one expressing high levels of episialin (F8), both in a variety of glandular epithelia.

Results

Juvenile mice, either transgenic or not, showed significant growth retardation at day 13 of age if fostered by a F8 transgenic mother. In the F8 mammary gland, large intracellular fat droplets were present just beneath the apical membrane of the luminal epithelial cells. In addition, the fat content in milk of fostering F8 transgenic mice was significantly reduced. This suggests that the accumulation of large intracellular fat droplets is the result of hampered fat secretion machinery in the mammary glands of these transgenic mice. Moreover, the mammary glands of the F8 transgenic mice already showed histological signs of premature involution after 13 days of lactation. Moreover, lactoferrin levels in milk of mice lactating for 13 days were higher in F8 mice than in nontransgenic mice, confirming that episialin overexpression induces premature involution.

Conclusion

Overexpression of episialin strongly inhibits fat secretion, and critically affects timing of involution of the lactating mammary gland.