Tumor progression and metastasis contribute to the great majority of breast cancer deaths. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in tumor progression and metastasis. Thus, we determined whether the expression of MMP-9 and TIMP-1 is associated with prognosis in breast cancer patients. We measured serum MMP-9 and TIMP-1 by enzyme-linked immunosorbent assay in 60 breast cancer patients, 18 benign breast disease patients and 15 healthy controls. We also evaluated the expression of MMP-9 and TIMP-1 protein and mRNA in paraffin-embedded tumor tissues from the 60 breast cancer patients by immunohistochemistry and in situ hybridization. We then correlated serum and tissue levels of MMP-9 and TIMP-1 in breast cancer samples and their expression with patients' clinicopathologic characteristics. We found that serum levels of MMP-9 and TIMP-1 were significantly higher in breast cancer patients than in benign breast disease and in healthy controls. High serum levels of MMP-9 and TIMP-1 were associated with lymph node metastasis, higher tumor stage and lower relapse-free and overall survival (OS) rates. Compared to low expression, high tissue expression of MMP-9 protein was associated with lymph node metastasis and higher tumor stage; and high tissue expression of TIMP-1 was associated with a lower OS rate. Our findings suggest that MMP-9 and TIMP-1 may further be evaluated as biomarkers for predicting progression and prognosis of breast cancer. ' 2008 Wiley-Liss, Inc.Key words: MMP-9; TIMP-1; breast cancer; serum biomarker; patient survival Breast cancer is one of the most common neoplasias in women worldwide. However, despite considerable diagnostic and therapeutic advances in recent years, it is still the most common cause of cancer death in women aged 40-49 years in the United States. 1 Approximately 40% of patients with localized breast cancer have micrometastatic disease that is difficult to detect at the time of diagnosis and treatment (especially during adjunctive therapy after surgery) and results in disease recurrence and death several years after diagnosis. 2-4 Serum biomarkers would be valuable in the early diagnosis of breast cancer; they would also be useful to clinicians in detecting micrometastasis and determining the risk of recurrence. This information would also help clinicians determine suitable therapy.Matrix metalloproteinases (MMPs) are a large family of highly homologous, zinc-and calcium-dependent extracellular enzymes that can be loosely categorized as matrilysin, gelatinases, stromelysin, collagenases or membrane-type MMPs on the basis of substrate specificity, protein domain structure, sequence homologic characteristics and ability to be secreted. 5-7 MMP-9 is one of the 2 gelatinases that has been implicated in tumor cell invasion and metastasis because of its unique ability to degrade Type IV collagen (a major component of the basement membrane) and other essential extracellular matrix components. 8,9 MMP-9 and its natural...
BACKGROUND:Different microRNAs have been shown to have oncogenic and tumor‐suppressive functions in human cancers. Detection of their expression may lead to identifying novel markers for breast cancer.METHODS:The authors detected miR‐340 expression in 4 human breast cell lines and then focused on its role in regulation of tumor cell growth, migration, and invasion and target gene expression. They then analyzed miR‐340 expression in benign and cancerous breast tissue specimens.RESULTS:Endogenous miR‐340 expression was down‐regulated in the more aggressive breast cancer cell lines, which was confirmed in breast cancer tissue specimens by using quantitative real‐time polymerase chain reaction. Further studies showed that induction of miR‐340 expression was able to suppress tumor cell migration and invasion, whereas knockdown of miR‐340 expression induced breast cancer cell migration and invasion. At the gene level, the authors identified c‐Met as a direct miR‐340 target to mediate cell migration and invasion through regulation of MMP‐2 and MMP‐9 expression. Ex vivo, loss of miR‐340 expression was associated with lymph node metastasis, high tumor histological grade, clinical stage, and shorter overall survival of breast cancer as well as increased c‐Met expression in breast cancer tissue specimens.CONCLUSIONS:miR‐340 may play an important role in breast cancer progression, suggesting that miR‐340 should be further evaluated as a novel biomarker for breast cancer metastasis and prognosis, and potentially a therapeutic target. Cancer 2011. © 2011 American Cancer Society.
BackgroundPreviously, we reported that polyploid giant cancer cells (PGCCs) induced by cobalt chloride (CoCl2) could have generated daughter cells with strong invasiveness and migration capabilities via asymmetric divisions. This study compared the expression of epithelial-mesenchymal transition (EMT)-related proteins, including E-cadherin, N-cadherin, and vimentin, between PGCCs and their daughter cells, and control breast cancer cell lines MCF-7 and MDA-MB-231. The clinicopathological significance of EMT-related protein expression in human breast cancer was analyzed.MethodsWestern blot was used to compare the expression levels of E-cadherin, N-cadherin, and vimentin in breast cancer lines MCF-7 and MDA-MB-231, between PGCCs with budding daughter cells and control breast cancer cells. Furthermore, 167 paraffin-embedded breast tumor tissue samples were analyzed, including samples obtained from 52 patients with primary breast cancer with lymph node metastasis (group I) and their corresponding lymph node metastatic tumors (group II), 52 patients with primary breast cancer without metastasis (group III), and 11 patients with benign breast lesions (group IV). The number of PGCCs was compared among these four groups.ResultsThe number of PGCCs increased with the malignant grade of breast tumor. Group IIhad the highest number of PGCCs and the differences among group I, II, III and IV had statistically significance (P =0.000). In addition, the expression of E-cadherin (P = 0.000), N-cadherin (P = 0.000), and vimentin (P = 0.000) was significantly different among the four groups. Group II exhibited the highest expression levels of N-cadherin and vimentin and the lowest expression levels of E-cadherin.ConclusionsThese data suggest that the number of PGCCs and the EMT-related proteins E-cadherin, N-cadherin, and vimentin may be valuable biomarkers to assess metastasis in patients with breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0277-8) contains supplementary material, which is available to authorized users.
Screening of the entire let-7 family of microRNAs (miRNA) by in situ hybridization identified let-7g as the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in otherwise nonmetastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, Grb2-associated binding protein 2 (GAB2) and fibronectin 1 (FN1), and consequent activation of p44/42 mitogenactivated protein kinase (MAPK) and specific matrix metalloproteinases. Treatment with estrogen or epidermal growth factor specifically reduced the expression of mature let-7g through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which, in turn, promoted tumor invasion. We thus identify let-7g as a unique member of the let-7 miRNA family that can serve as a prognostic biomarker in breast cancer and also propose a paradigm used by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis. Thus, let-7 family members neither possess equivalent clinicopathologic correlation nor function in breast cancer. Cancer Res; 71(20); 6463-74. Ó2011 AACR.
This is the largest study of hPSCs in nonhuman primates in cardiovascular field to date (n=32). Compared with cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better recovery of left ventricular function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.
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