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: Yasunori Hoshiya, Vandana Gupta, Hirofumi Kawakubo, Elena Brachtel, Jennifer L Carey, Laura Sasur, Andrew Scott, Patricia K Donahoe, Shyamala Maheswaran
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 51 Pg. 51703-12 (Dec 19 2003) ISSN: 0021-9258 [Print] United States
• PMID: 14532292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Glycoproteins
• IRF1 protein, human
• Interferon Regulatory Factor-1
• Irf1 protein, mouse
• Irf1 protein, rat
• Phosphoproteins
• Testicular Hormones
• activin A
• Activins
• Anti-Mullerian Hormone
• Interferon-gamma
• Inhibin-beta Subunits

Topics

• Activins (pharmacology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Anti-Mullerian Hormone
• Apoptosis (drug effects)
• Biopsy
• Breast Neoplasms (pathology)
• Cell Division (drug effects)
• Cell Line, Tumor
• DNA-Binding Proteins (analysis, biosynthesis)
• Drug Synergism
• Female
• Gene Expression Regulation (drug effects)
• Glycoproteins (pharmacology)
• Humans
• Inhibin-beta Subunits (pharmacology)
• Interferon Regulatory Factor-1
• Interferon-gamma (pharmacology)
• Mice
• Mice, Inbred C3H
• Middle Aged
• Phosphoproteins (analysis, biosynthesis)
• Rats
• S Phase (drug effects)
• Testicular Hormones (pharmacology)