Mullerian Inhibiting Substance (MIS) Augments IFN-Gamma Mediated Inhibition of Breast Cancer Cell Growth
Abstract
Mullerian inhibiting Substance (MIS) is a member of the TGFbeta family, a class of molecules that govern a myriad of cellular processes including growth, differentiation, and apoptosis. In male embryos, MIS causes regression of the Mullerian duct. We have recently demonstrated the presence of MIS receptors in mammary tissue and in breast cancer cell lines suggesting that the mammary gland is a likely target for MIS. MIS inhibited the growth of both ER positive and negative breast cancer cells by inducing cell cycle arrest and apoptosis. We have demonstrated that MIS promotes IFN-gamma-induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer breast cancer cell growth. To evaluate whether MIS and IFN-gamma may be useful in breast cancer therapy, we determined whether the growth inhibitory effect of MIS and IFN-gamma observed in vitro would be recapitulated in vivo. The C3(1)Tag transgenic mouse model carries the SV40 large T antigen targeted to the epithelium of the mammary and prostate glands and progression of disease in these animals correlates well with progressive stages of human breast cancer. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (p-0.048), and the mean mammary tumor weight in the Ml S-treated group was significantly lower compared with the control group (p-0.029). Analysis of PCNA expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and not due to decline in T-antigen expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA442337
Entities
People
- Vandana Gupta
Organizations
- Massachusetts General Hospital