title: Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis.
abstract: OBJECTIVE
  Breast cancer (BC) is the most common type of cancer in Saudi women. Matrix metalloproteinases (MMPs) are endopeptidases with the ability to degrade extracellular matrix proteins. In healthy individual tissue disruption is prevented by precised regulation of MMPs; however, in cancer a number of MMPs are overexpressed causing tissue disruption and making tumor cells capable of invasion and metastasis. Invasive ductal carcinoma (IDC) of BCs are classified into grade 1 (G1), grade 2 (G2) and grade 3 (G3) tumors.
  
  
  METHODS
  We performed a transcriptomic profiling of 38 surgically-resected breast tumors (4 G1, 17 G2 and 17 G3) using Affymetrix Gene 1.0 ST microarrays. Differentially expressed genes for each grade were identified by the Partek Genomic Suite 6.4 and expression analysis results were validated by immunohistochemistry at the protein level. Pathway analyses and establishment of clinical significance of findings were performed using the appropriate software.
  
  
  RESULTS
  We identified 1,593 differentially expressed genes in BC grades in comparison to normal samples using a cut-off of p<0.05 and fold change >2. Out of these genes 429 were expressed throughout in all grades along with tumor progression while many others associated with specific grades (440 genes in G1, 203 in G2 and 394 in G3 only) were exclusively. Microarray results indicate that mRNA expression of MMP-1, -9,-11,-12, and -13 were up-regulated in higher BC grades when compared to normal breast tissues. MMP-9 was expressed in most IDC (97.5%) samples and was highly expressed in 55% of the tumors. Differential expression of MMP-9 significantly correlated with histological BC grades of (p=0.03) and strongly correlated with overall survival (p=0.08).
  
  
  CONCLUSIONS
  Gene expression signatures are unique for specific grades. Overexpression of MMPs in higher grades might be associated with BC tumor invasion and metastasis. Therefore, MMPs, and MMP-9 in particular, are reliable candidates for diagnostic biomarker and drug target and further functional analyses have to be performed in order to confirm their role in BC. Our results also suggest the incidence of MMP-9 expression is high in IDC, but it is of limited prognostic value.
authors.affiliation: King Abdulaziz University, PO BOX 80216, Jeddah 21589, Kingdom of Saudi Arabia. Tel: +966 126401000 ext 25123, skarim1@kau.edu.sa; sajjad_k_2000@yahoo.com.
authors.forename: Adnan
authors.initials: A
authors.lastname: Merdad
authors.forename: Sajjad
authors.initials: S
authors.lastname: Karim
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Schulten
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dallol
authors.forename: Abdelbaset
authors.initials: A
authors.lastname: Buhmeida
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Thubaity
authors.forename: Mamdooh A
authors.initials: MA
authors.lastname: Gari
authors.forename: Adeel Ga
authors.initials: AG
authors.lastname: Chaudhary
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Al-Qahtani
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011812:Quinuclidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D011812:Quinuclidines; D012333:RNA, Messenger; D051176:beta Catenin; D020782:Matrix Metalloproteinases
keywords: Breast cancer; MMP-9; MMPs; Saudi Arabia; gene expression; histological grade; invasive ductal carcinoma