title: Mullerian inhibiting substance promotes interferon gamma-induced gene expression and apoptosis in breast cancer cells.
abstract: 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.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hoshiya
authors.forename: Vandana
authors.initials: V
authors.lastname: Gupta
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kawakubo
authors.forename: Elena
authors.initials: E
authors.lastname: Brachtel
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Carey
authors.forename: Laura
authors.initials: L
authors.lastname: Sasur
authors.forename: Andrew
authors.initials: A
authors.lastname: Scott
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
mesh_terms: 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*
chemical_list: 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