P2-01-10: Blockage of Autocrine TGF-b Signaling Reduces Tumorigenecity and Lung Metastasis in a Murine Breast Cancer Cell Line, NMuMG-ST.

Abstract

Abstract Transforming growth factor beta (TGF-b) is known to have a dualistic role in breast cancer cells, acting as a tumor suppressor or a tumor promoter. This dualistic property varies in different cells and at different progression stages. Studies show that autocrine TGF-b is necessary for the growth and survival of MDA-MB-231 cells, and was also known to enhance the survival of MCF-7 cells. However, the role of autocrine TGF-b in spontaneously transformed cells is still less understood. We have retrovirally transduced a dominant negative TGF-b Type II receptor (DN RII) into a spontaneously transformed murine mammary gland epithelial cell line NMuMG-ST (DN RII cells). The expression of DN RII reduces TGF-b sensitivity of NMuMG-ST cells in a gene transcription assay and a growth inhibition assay. Interestingly, the autocrine TGF-b supports the survival of NMuMG-ST cells, although the exogenous TGF-b inhibits the growth of NMuMG-ST cells. Moreover, more apoptosis were observed in the DN RII cells compared to the control cells in both in vivo and in vitro experiment. We found that AKT and ERK pathway mediates autocrine TGF-b's survival signal. Results of western immunoblot for several stem cell markers and mammosphere formation assay suggest that autocrine TGF-b signaling is essential for the maintenance of stem like cell subpopulation in NMuMG-ST cells. By using immunocytostaining, we found that the DN RII cells expressed more E-cadherin and less Vimentin when compared to the control NMuMG-ST cells, which indicate that blocking autocrine TGF-b signaling pathway could inhibit the process of EMT in NMuMG-ST cells. Notably, when the cells were inoculated orthotopically in nude mouse mammary glands, tumors formed by DN RII cells grew at a similar rate as those formed by control cells, but caused fewer lung metastases. Our finding identified that the autocrine TGF-b signaling is important for the survival and metastatic ability of NMuMG-ST, which could provide an important foundation for further investigation on the role of autocrine TGF-b signaling in breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-10.