Mullerian Inhibiting Substances (MIS) Augments IFN-gamma Mediated Inhibition of Breast Cancer Cell Growth

摘要

MIS is a member of the TGF family. 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 than either agent alone. We observed MIS and IFN-gamma costimulate IRF1 expression through NFkB and STAT pathways, respectively with a synergistic induction of CEACAM1 and MHCII mRNA expression, benisons of IRF1. 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. We observed that MIS promotes IFN-gamma-induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer cell growth. To evaluate whether MIS and IFN-gmay be useful in breast cancer therapy, we determined whether the growth inhibitory effect of MIS and IFN-gamma observed in vitro would berecapitulated in vivo. Both MIS and IFN-gamma decreased the gain in tumor volume of MDAMB468 xenografts established in SCID mice. 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. Administration of MIS to mice was associated with a lower number of palpable mammary tumors and the mean mammary tumor weight as compared with the control group (p=0.029). Different doses of mIFN-gwere injected into 10 week old C3(1)Tag transgenic mice for 5 weeks intraperitoneally. Both 10ng and 100ng mIFN-gamma significantly reduced the tumor volumes and tumor weights in this mouse model. Analysis of PCNA expression and caspase-3 cleavage in tumors revealed that exposure to MIS or mIFN-gamma was associated with decreased proliferation and increased apoptosis, respectively.