Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells.
OBJECTIVE
To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition.


METHODS
Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)].


RESULTS
IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA.


CONCLUSIONS
These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.|b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.
Francisco
F
Artacho-Cordón
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.|b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.|c Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada , Armilla, Granada , Spain.
Sandra
S
Ríos-Arrabal
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.
María Auxiliadora
MA
Olivares-Urbano
d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.|e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.|f German Cancer Consortium (DKTK), Dresden, Germany.|g German Cancer Research Center (DKFZ) , Heidelberg , Germany.|h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.
Katja
K
Storch
d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.|e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.|f German Cancer Consortium (DKTK), Dresden, Germany.|g German Cancer Research Center (DKFZ) , Heidelberg , Germany.|h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.
Ellen
E
Dickreuter
b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.|i CIBER on hepatic and digestive diseases (CIBEREHD) , Spain.
José Antonio
JA
Muñoz-Gámez
b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.|i CIBER on hepatic and digestive diseases (CIBEREHD) , Spain.
Josefa
J
León
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.|b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.
Irene
I
Calvente
j General Surgery Management Unit, San Cecilio University Hospital , Granada , Spain.
Pablo
P
Torné
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.
María del Mar
Mdel M
Salinas
d OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, and Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.|e Department of Radiation Oncology , University Hospital Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.|f German Cancer Consortium (DKTK), Dresden, Germany.|g German Cancer Research Center (DKFZ) , Heidelberg , Germany.|h Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.
Nils
N
Cordes
a Department of Radiology and Physical Medicine , University of Granada , Granada , Spain.|b Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada/University of Granada , Granada , Spain.|c Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada , Armilla, Granada , Spain.
María Isabel
MI
Núñez
D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007259:Infrared Rays / Q000627:therapeutic use; D061986:MCF-7 Cells; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014635:Valproic Acid; D020782:Matrix Metalloproteinases
Matrix metalloproteinases; breast cancer; epigenetic regulation; histone deacetylases; invasion; ionizing radiation; tumour microenvironment