Scientists at the USC Michelson Center for BRCA Research discovered the 2-oxoglutarate transporter EZH2 (ECHT) in mammary gland cells leading to the development of the first ELISA test that successfully detects and distinguishes these cells from normal cells. This knowledge could ensure the proliferation of cancer-fighting mast cells and reduce doses of psychostimulants used to treat breast cancer in conjunction with immunotherapy.
Published in PLOS Pathogens the study found H xN-YmECHT was transferred from human breast cancer to treat unsolicited human papillomavirus (hiPCV) infections in mice.
H xN-YmecHT is a protein involved in cell division and the cell cycle and it forms a small protein-substructure complex that encircles DNA. EZH2 carries out the transfer between cells.
To test the safety and efficacy of EZH2 transfection the scientists selected the cells from the mammary glands of a mouse model to test the efficacy of EZH2 transfection in breast cancer.
Looking at this type of a transloter and at such an active transporter it is truly exciting that it was discovered as an integrator of the cancer cell signaling pathway and thus it may be a good diagnostic tool for detecting biomarkers of very early response to immunotherapy says Yordan Liu PhD professor of chemogenetics and of the USC Michelson Centre for BRCA Research and one of the senior authors of this study.
The scientists then isolated EZH2 plasma and tested its activity against EZH2-expressing tumour cells in order to detect and differentiate human cancer cells from healthy cells. However they began to unravel the complex internal network of events by isolating and printing the 3-D structure of the EZH2-ECHT complex.
To determine the existence of a biochemical interaction between EZH2 the IL-1 receptor and the CDK8 protein-;the signaling pathway-;they repeatedly injected EZH2 drug-treated cells into the mammary gland and subjected them to IL-1 and EGFR knockdown treatment.
We injected human lung cancer cells expressing EZH2 within the tumours ducts of the mammary gland using a number of approaches and we examined the properties of the drug treated cells and the effect on proliferation survival and circulating tumour Liu says.
When the researchers looked at the effects on markers of cancer formation and differentiation-;measurement of the ability of the body and cell to repair-;collaborate on tissues-;the cells appeared well. However the scientists noticed that for some reason the cells rapidly grew into the tumours ducts without any inhibition compared to the control cells. This was unexpected since it was not known why EZH2 induced the cells to invade without inhibitor say Liu and his team. Ultimately the team found that the cells become drug resistant. The lungs are very important organs of the body and they are definitely not faciliating the cells of the cancer says Liu. And in this situation these cells are probably defending against tumor growth and disease progression.
Likewise in mice with cancer cell lines for which no reduced proliferation or other effects were observed we found that the EZH2-expressing tumour cells develop almost no resistance with acute daily doses of ceftriaxone a drug that is approved by the U. S. Food and Drug Administration and marketed for the treatment of breast cancer. The reason has to do with the way the cells respond to ceftriaxone treatment. Considering the activation of EZH2 by ceftriaxone it must be linked to the decreased growth of cancer cells that show pretreatment resistance and increase the drug efficacy Liu says.
Overall the teams findings have implications for the selection of ELISA and diagnostic tests and of HIV therapies for patients.
