Mullerian inhibiting substance promotes interferon gamma-induced gene expression and apoptosis in breast cancer cells.
This report demonstrates that in addition to interferons and cytokines, members of the TGF beta superfamily such as Mullerian inhibiting substance (MIS) and activin A also regulate IRF-1 expression. MIS induced IRF-1 expression in the mammary glands of mice in vivo and in breast cancer cells in vitro and stimulation of IRF-1 by MIS was dependent on activation of the NF kappa B pathway. In the rat mammary gland, IRF-1 expression gradually decreased during pregnancy and lactation but increased at involution. In breast cancer, the IRF-1 protein was absent in 13% of tumors tested compared with matched normal glands. Consistent with its growth suppressive activity, expression of IRF-1 in breast cancer cells induced apoptosis. Treatment of breast cancer cells with MIS and interferon gamma (IFN-gamma) co-stimulated IRF-1 and CEACAM1 expression and synergistic induction of CEACAM1 by a combination of MIS and IFN-gamma was impaired by antisense IRF-1 expression. Furthermore, a combination of IFN-gamma and MIS inhibited the growth of breast cancer cells to a greater extent than either one alone. Both reagents alone significantly decreased the fraction of cells in the S-phase of the cell cycle, an effect not enhanced when they were used in combination. However, MIS promoted IFN-gamma-induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer cell growth.
Hoshiya
Yasunori
Y
Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gupta
Vandana
V
Kawakubo
Hirofumi
H
Brachtel
Elena
E
Carey
Jennifer L
JL
Sasur
Laura
L
Scott
Andrew
A
Donahoe
Patricia K
PK
Maheswaran
Shyamala
S
D028341:Activins / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054304:Anti-Mullerian Hormone; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D010750:Phosphoproteins / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D016196:S Phase / Q000187:drug effects; D013735:Testicular Hormones / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D006023:Glycoproteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C494259:Irf1 protein, rat; D010750:Phosphoproteins; D013735:Testicular Hormones; C422405:activin A; D028341:Activins; D054304:Anti-Mullerian Hormone; D007371:Interferon-gamma; D028322:Inhibin-beta Subunits