Our project’s topic illustrates how AMF induces phosphorylation of the HER2 receptor and thus activates its signaling pathway. HER2 breast cancer is when the breast cancer cells have an amplification of HER2 2 receptors on the surface of the cell. With this increased number of receptors cell proliferation is increased resulting in cancer. HER2 breast cancer is often treated with the Trastuzumab(Herceptin) drug. This drug works by first attaching onto the HER2 receptor on the extracellular side, which then stops the receptors from signaling downstream. Many patients who take Herceptin become resistant to its effects. My group will explore the theory that the interaction between AMF and HER2 causes the resistance to the drug. AMF’s phosphorylation of HER2 activates phosphoinositide-3-kinase and mitogen-activated protein kinase signaling. This happens regardless of Herceptin involvement. This is important because the AMF-HER 2 interaction may be a viable target for therapeutic treatment of patients with breast cancer.
AMF has many other aliases; these include glucose-6-phosphate, the enzyme that catalyzes the conversion of glucose-6-phosphate into fructose 6-phosphate in the second step of glycolysis, and neuroleukin which is a neurotrophic factor for spinal and sensory neurons. Though AMF and the others, GPI and NLK, have differing functions they all come from the same gene. AMF monomers are made of two domains, both these domains are in a alpha-beta-alpha conformation. The smaller domain contains a five-stranded beta-sheet surrounded by alpha helices. The larger domain has a six-stranded beta sheet. The functional AMF dimer is composed of two identical monomers. The active site of each monomer is created by a cleft between the to domains and the dimer interface.
AMF is part of a group of cytokines that stimulates tumor cell motility in an autocrine fashion. This protein factor is expressed and secreted by cancer cells via an autocrine route. This action has been known to stimulate the motility of cancer cells. Malignant tumors can often be characterized by their unregulated growth, invasion into local areas, and their eventual growth into distant organs. One can conclude that for any of these goals to be accomplished the tumor needs to have an efficient cell migration mechanism. AMF was distinguished among the cytokines due to its ability to stimulate directional and random motility of AMF producing cells.
Recent trials conducted by the forerunners of AMF research found that AMF and its receptor AMFR have a direct link with breast cancer. High levels of AMF and AMFR were found in patients who died of breast cancer, and also in those who had reoccurrence. Also a significant relationship was found between high levels of AMF and long-term survival. The researchers concluded that AMF and AMFR are overexposed in breast cancer and have a negative association with the patients long term outcome. This confirms their belief that the AMF-AMFR complex has a significant role in the progression and severity of breast cancer. Along with these characteristics AMF also protects cancer cells from undergoing apoptosis and is involved in up regulation of cyclin dependent kinase activity, which we learned about in the beginning of this quarter.
In a recent immunohistochemical staining of AMF test the scientists found evidence that AMF and AMFR levels had a direct link to the growth of tumors. In stromal and endothelial cells the staining for AMF was weak, while in tumor tissues the staining was high in both the cytoplasm and the nucleus. Vascular endothelial cells and larger vascular vessels in tumor tissues also had a high degree of staining. This means that AMF and its receptor were prevalent in the vascular system, which confirms that AMF does indeed have a connection to metastasis. The graph above shows the actual immunohistochemical staining data of tumor cells versus normal cells. The AMF is were the black arrows are, and they are clearly present in the tumor cells but not in the normal cells.
Knowing what we know about AMF we can conclude that the AMF and HER 2 relationship may be a target for future therapeutic drugs. If we can design a drug that can either disrupt AMF so that it loses its affinity for HER 2 or one that deactivates AMF all together we may be able to actually stop this resistance to herceptin from forming. Another method may be in finding a way to disrupt one of the many signaling pathways such as MAPK, which are triggered from HER2 phosphorylation, but that is another topic.
1. Liotta LA, Mandler R, Murano G, Katz DA, Gordon RK, Chiang PK, Schiffmann E (May 1986). "Tumor cell autocrine motility factor". Proc Natl Acad Sci U S A 83 (10): 3302–6. doi:10.1073/pnas.83.10.3302. PMID 3085086.
2. Raz, Avraham, Yi Wang, Larry Tait, and Victor Hogan. "Autocrine Motility Factor Promotes HER2 Cleavage and Signaling in Breast Cancer Cells."- Autocrine Motility Factor Promotes HER2 Signaling. N.p., n.d. Web. 30 May 2014.
3. Silletti S, Raz A (July 1993). "Autocrine motility factor is a growth factor". Biochem Biophys Res Commun. 194 (1): 454–5. doi:10.1006/bbrc.1993.1840.PMID 8392842.
4. Watanabe H, Takehana K, Date M, Shinozaki T, Raz A (July 1996). "Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide". Cancer Res. 56 (13): 2960–3. PMID 8674049.