Expression Of Nuclear Factor κB In Breast Cancer And Its Role In Promoting Cancer Metastasis Discipline Of Oncology

The nuclear factor kB (NF-kB) was first identif ided in 1986 as the transcription factor involved inB lymphocyte-specific expression of k-immunogIobulin light chain. Subsequent studies revealed ubiquitous activity of NF-kB and >180 target genes, who play an important role in the regulation of immune response, embryo and cell lineage development, careigenes is, apoptosis, resistance to radiochemotherapy, proliferation, differentiation, cell migration , invasiveness, angiogenesis and metastas i s etc.Many studies showed NF-kB is constitutively overexpressed in variou tumors~[1], including breast cancer, prostate cancer, multiple myeloma, ovar i an cancer, gastric cancer, colorectal cancer, hepatic cancer etc. blocking NF~kB activation could enhance the effects of cytotoxic chemotherapy and down-regulate tumor metastasis. The metastasis of malignant cells is a multistep process involving (1) extracel lular matrix degradation and subsequent detachment of cancer cells from the primary tumor; (2) invasion of surrounding tissue; (3) penetration of blood and/or lymphatic vessels (a I so called intravasation) ; (4) survival in the blood ci rculation, transport to new sites, and arrest of cancer cells in the microcirculation; (5) migration of cancer cells through the vessel wall into the interstitial space (extravasation); and (6) proliferation of cancer cells in the target organs (colonization).Two mutually dependent protease systems are required for extracellular matrixdegradation. The first system includes MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13. These proteins are secreted as pro-MMPs, and most of them are activated by the second protease system. The second system involves the uPA/urokinase plasminogen activator receptor (uPAR)/plasminogen system. The uPA/uPAR converts plasminogen to plasmin, which activates MMPs. The uPA/uPAR and MMP-9 are essential for intravasation of a number of cancer cell lines, including MDA-MB-231 breast cancer cells. Although overexpression of uPA/uPAR/MMP-9 is not necessary for survival and attachment of cancer cells to the microvasculature, overexpression of uPA/uPAR is essential for migration and colonization at the target site. NF-kB can promote extracellular matr ix degradation, migration, and colonization at the target site by directly inducing the expression of uPA and MMP-9, thereby increasing metastasis. NF-kB has also been shown to increase the expression of prometastatic heparanase and decrease the expression of antimetastatic tissue inhibitors of MMP-1 and MMP-2 and plasminogen activatorinhibitor.However, systemical study on NF-kB expression and its association with uPA and MMP9 in both breast cancer specimens and cell model is rarely reported till now. Soin this paper, the above was investigated so as to shed light on the mechanism ofNF-kB involved in breast cancer metastasis.Part I : Expression of NF-kB in breast cancer specimens and its clinical significance Purpose.To investigate the expression and activation of nuclear factor kB in breast caner specimens and its association with breast cancer clinical pathology. Materials and Methods: A total of 46 lumpectomy and mastectomy samples from breast cancer patients, were separated into tumor tissue (T) and normal adjacent tissue (A) by a pathologist in No. 2 hospital affiliated to our University. The samples were collected principaly from 2001 to 2002, all female, invasive type (a fraction from Sir Run Run Shaw hospital in May 2004). Age range from 31 years old to 81 years old, median 49. 5 years old. Immunohistochemistry (IHC), Western blot (WB) and DIG-label ledElectrophoretic mobility shift assay (EMSA) were performed to detect the expression and activation of nuclear factor kB. Results: Constitutive Nuclear trans location of RelA (marker of NF-kB activation) in 67.4% (31/46) of breast cancer tissues in the method of IHC. Additionally, NF-kB p65 expression and activation in nuclear extract was significantly higher in tumor tissue as compared to adjacent tissue by WB and EMSA. Negative correlation between NF-kB p65 and ER a status (r=-...