Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth.
Human dendritic cells (DCs) stimulated with cytokines and LPS down regulate the expression of proto-oncogene HER-2/neu and GPI linked protein CD24 in breast cancer cell lines.
These results suggest for the first time that PGI/AMF is a key gene to both EMT in the initiating step of cancer metastasis and MET in the later stage of metastasis during breast cancer progression.
High levels of AMF and AMFR were seen in patients who died of breast cancer (p=0.049, p=0.0435) and high AMF was also seen in patients who had local recurrence (p=0.039) compared with those who remained disease free.
We establish here that in the human breast carcinoma BT-549 cells hypoxia enhanced expression of the transcription factor hypoxia-inducible factor (HIF)-1, which in turn led to the up-regulation of PGI/AMF expression and was specifically inhibited by inhibitors of the phosphatidylinositol 3'-kinase signaling pathway.
Treatment of breast cancer cells with the combination of HCT and specific AMF inhibitors, erythrose 4-phosphate or D-mannose 6-phosphate, resulted in an additive inhibitory effect on both the growth rate and invasiveness of cells as compared with treatment with each agent alone.
The present study is the first demonstration of AMF regulation by a growth factor and suggests a potential role for AMF in HRG regulation of breast cancer cell motility and a novel function of HRG as a regulator of motility factor expression.