Mullerian Inhibiting Substance (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth
Abstract
Mullerian Inhibiting Substance (MIS), a member of the TGFB family regulates growth, differentiation, and apoptosis in many cell types In the male embryo, MIS causes regression of the Mullerian duct. However, the presence of MIS type II receptor gene in the breast is suggestive of its postnatal role in breast. Although the antitumor effects of IFN-gamma are well documented, toxic effects associated with IFN-gamma have precluded its use in the treatment of cancer patients: The purpose of this study is to test the hypothesis that MIS and IFN-gamma might be more effective in the inhibition of breast cancer cell growth both in vitro and in vivo than either agent alone. Presently, we have observed that MIS and IFN-gamma function through distinct molecular pathways. MIS induced NFkB DNA binding activity in breast cancer cells where as IFN-gamma functions through Stat pathway as is observed using IkBa-DN clones. Co- stimulation of IRF-1 by MIS and IFN-1 in breast cancer cells is mediated through activation of NFkB and STAT pathways, respectively and is independent of Smadi phosphorylation. The simultaneous addition of MIS and IFN-gamma resulted in synergistic induction of CEACAMi expression in T47D cells. In concordance with this observation, treatment of MDA-MB-468 cells with either MIS or IFN-gamma inhibited growth and the presence of both inhibited growth better over a period of eight days. However, the enhanced inhibition of breast cancer cell growth by MIS and IFN-gamma could not be explained by combined changes in cell cycle progression as 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA428316
Entities
People
- Shyamala Maheswaran
- Vandana Gupta
Organizations
- Massachusetts General Hospital