Mullerian inhibiting substance regulates NF kappa B signaling and growth of mammary epithelial cells in vivo

Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro through interference with cell cycle progression and induction of apo ptosis, a process associated with NF kappaB activation and up-regulation of one of its important target genes, IEX-1S (Segev, D. L., Ha, T., Tran, T. T., Kenneally, M., Harkin, P., Jung, M., MacLaughlin, D. T., Donahoe, P. K. , and Maheswaran, S. (2000) J. Biol. Chem. 275, 28371-28379). Here we demon strate that MIS activates the NF kappaB signaling cascade, induces IEX-1S m RNA, and inhibits the growth of MCF10A, an immortalized human breast epithe lial cell line with characteristics of normal cells. In vivo an inverse cor relation was found to exist between various stages of mammary growth and MI S type II receptor expression. Receptor mRNA significantly diminished durin g puberty, when the ductal system branches and invades the adipose stroma a nd during the expansive growth at lactation, but it was up-regulated during involution, a time of regression and apoptosis. Peripartum variations in M IS type II receptor expression correlated with NF kappaB activation and IEX -1S mRNA expression. Administration of MIS to female mice induced NF kappaB DNA binding and IEX-1S mRNA expression in the breast. Furthermore, exposur e to MIS in vivo increased apoptosis in the mouse mammary ductal epithelium . Thus, MIS may function as an endogenous hormonal regulator of NF kappaB s ignaling and growth in the breast.