Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary epithelial cells in vivo.
Müllerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro through interference with cell cycle progression and induction of apoptosis, a process associated with NFkappaB 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 demonstrate that MIS activates the NFkappaB signaling cascade, induces IEX-1S mRNA, and inhibits the growth of MCF10A, an immortalized human breast epithelial cell line with characteristics of normal cells. In vivo, an inverse correlation was found to exist between various stages of mammary growth and MIS type II receptor expression. Receptor mRNA significantly diminished during puberty, when the ductal system branches and invades the adipose stroma and during the expansive growth at lactation, but it was up-regulated during involution, a time of regression and apoptosis. Peripartum variations in MIS type II receptor expression correlated with NFkappaB activation and IEX-1S mRNA expression. Administration of MIS to female mice induced NFkappaB DNA binding and IEX-1S mRNA expression in the breast. Furthermore, exposure to MIS in vivo increased apoptosis in the mouse mammary ductal epithelium. Thus, MIS may function as an endogenous hormonal regulator of NFkappaB signaling and growth in the breast.
Segev
D L
DL
Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Hoshiya
Y
Y
Stephen
A E
AE
Hoshiya
M
M
Tran
T T
TT
MacLaughlin
D T
DT
Donahoe
P K
PK
Maheswaran
S
S
D000818:Animals; D054304:Anti-Mullerian Hormone; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D017931:DNA Primers; D004847:Epithelial Cells / Q000378:metabolism; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013735:Testicular Hormones / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D006023:Glycoproteins; D006131:Growth Inhibitors; C099815:IER3 protein, human; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone