Interfering Breast Cancer Metastasis by Blocking NGAL Function
Final rept. 1 Sep 2008-31 Aug 2011
M D ANDERSON CANCER CENTER HOUSTON TX
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NGAL project was initiated based on the genome-wide transcript analysis using RNA samples of 318 breast cancer patients diagnosed in MD Anderson Cancer Center. We found that the transcript of NGAL from the tumor mass correlates with advanced tumor stage, metastatic status and other poor clinical indexes. NGAL neutrophil gelatinase associated lipocalin is a glycosylated secreted protein and it also can be detected at high concentration in the plasma of various types of cancer patients including breast cancer patients. We tested the function of NGAL in breast tumorigenesis using a spontaneous mammary tumor mouse model. Our data on LCN2 function in promoting mouse mammary tumor in vivo was published in Cancer Research 2009 Nov 1569228579-84 See Appendix I, which confirmed our hypothesis that NGAL is a driving factor for mammary tumor formation and metastasis. Our results are largely supported the later data from other labs. As requested by Journal of Cell physiology, we reviewed the progress in NGAL studies in breast cancer J Cell Physiol. 2011 Feb 2262309-14 See Appendix II. The goals of this DOD funding are to 1 develop methods to block NGAL function for producing a clinically applicable drug and 2 dissect the molecular mechanisms of how NGAL promote breast tumorigenesis. We have designed high throughput screen methods to identify small inhibitory chemical compounds blocking the interaction of NGAL and matrix metalloproteinase 9 MMP-9 or blocking NGAL entry into the cells. We constructed luciferase-expressing human breast tumor cell lines for future testing the NGAL inhibitors in vivo. For the second goal, we found that mouse mammary tumor lacking NGAL expression retained CK-18 a good prognostic marker expression. Reducing mouse NGAL expression greatly attenuated the invasive potential of 4T1 cells.
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