PMID- 22260435
OWN - NLM
STAT- MEDLINE
DCOM- 20120330
LR  - 20220331
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 12
DP  - 2012 Jan 19
TI  - TGF-beta1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK 
      and ERK1/2 in highly invasive breast cancer cells.
PG  - 26
LID - 10.1186/1471-2407-12-26 [doi]
AB  - BACKGROUND: Metastasis is the main factor responsible for death in breast cancer 
      patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue 
      inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are 
      essential for the metastatic process. We have previously shown a positive 
      correlation between MMPs and their inhibitors expression during breast cancer 
      progression; however, the molecular mechanisms underlying this coordinate 
      regulation remain unknown. In this report, we investigated whether TGF-beta1 could 
      be a common regulator for MMPs, TIMPs and RECK in human breast cancer cell 
      models. METHODS: The mRNA expression levels of TGF-beta isoforms and their receptors 
      were analyzed by qRT-PCR in a panel of five human breast cancer cell lines 
      displaying different degrees of invasiveness and metastatic potential. The highly 
      invasive MDA-MB-231 cell line was treated with different concentrations of 
      recombinant TGF-beta1 and also with pharmacological inhibitors of p38 MAPK and 
      ERK1/2. The migratory and invasive potential of these treated cells were examined 
      in vitro by transwell assays. RESULTS: In general, TGF-beta2, TbetaRI and TbetaRII are 
      over-expressed in more aggressive cells, except for TbetaRI, which was also highly 
      expressed in ZR-75-1 cells. In addition, TGF-beta1-treated MDA-MB-231 cells 
      presented significantly increased mRNA expression of MMP-2, MMP-9, MMP-14, TIMP-2 
      and RECK. TGF-beta1 also increased TIMP-2, MMP-2 and MMP-9 protein levels but 
      downregulated RECK expression. Furthermore, we analyzed the involvement of p38 
      MAPK and ERK1/2, representing two well established Smad-independent pathways, in 
      the proposed mechanism. Inhibition of p38MAPK blocked TGF-beta1-increased mRNA 
      expression of all MMPs and MMP inhibitors analyzed, and prevented TGF-beta1 
      upregulation of TIMP-2 and MMP-2 proteins. Moreover, ERK1/2 inhibition increased 
      RECK and prevented the TGF-beta1 induction of pro-MMP-9 and TIMP-2 proteins. 
      TGF-beta1-enhanced migration and invasion capacities were blocked by p38MAPK, ERK1/2 
      and MMP inhibitors. CONCLUSION: Altogether, our results support that TGF-beta1 
      modulates the mRNA and protein levels of MMPs (MMP-2 and MMP-9) as much as their 
      inhibitors (TIMP-2 and RECK). Therefore, this cytokine plays a crucial role in 
      breast cancer progression by modulating key elements of ECM homeostasis control. 
      Thus, although the complexity of this signaling network, TGF-beta1 still remains a 
      promising target for breast cancer treatment.
FAU - Gomes, Luciana R
AU  - Gomes LR
AD  - Departamento de Bioquimica, Universidade de Sao Paulo, Sao Paulo, Brazil. 
      mcsoga@iq.usp.br
FAU - Terra, Leticia F
AU  - Terra LF
FAU - Wailemann, Rosangela Am
AU  - Wailemann RA
FAU - Labriola, Leticia
AU  - Labriola L
FAU - Sogayar, Mari C
AU  - Sogayar MC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120119
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Blotting, Western
MH  - Breast Neoplasms/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Female
MH  - Homeostasis/drug effects
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects/physiology
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Matrix Metalloproteinases/*metabolism
MH  - Neoplasm Proteins/*metabolism
MH  - Polymerase Chain Reaction/methods
MH  - RNA, Messenger/metabolism
MH  - Tissue Inhibitor of Metalloproteinases/*metabolism
MH  - Transforming Growth Factor beta1/metabolism/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/*antagonists & inhibitors/pharmacology
PMC - PMC3277461
EDAT- 2012/01/21 06:00
MHDA- 2012/03/31 06:00
PMCR- 2012/01/19
CRDT- 2012/01/21 06:00
PHST- 2011/11/17 00:00 [received]
PHST- 2012/01/19 00:00 [accepted]
PHST- 2012/01/21 06:00 [entrez]
PHST- 2012/01/21 06:00 [pubmed]
PHST- 2012/03/31 06:00 [medline]
PHST- 2012/01/19 00:00 [pmc-release]
AID - 1471-2407-12-26 [pii]
AID - 10.1186/1471-2407-12-26 [doi]
PST - epublish
SO  - BMC Cancer. 2012 Jan 19;12:26. doi: 10.1186/1471-2407-12-26.