Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of Wwox expression.
OBJECTIVE
The WWOX gene is down-regulated in breast cancer and loss of Wwox expression correlates with important clinical features of breast cancer. Thus, we have examined the effect of restoration of Wwox expression in breast cancer-derived cells.


METHODS
Wwox protein expression was restored by the following: (a) infection with a recombinant adenovirus carrying WWOX cDNA (Ad-WWOX) or (b) treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, to activate the endogenous WWOX gene, in breast cancer-derived cells in vitro and in vivo.


RESULTS
Restoration of Wwox expression led to suppression of growth of Wwox-deficient breast cancer-derived cells, through activation of the intrinsic caspase pathway, but did not affect growth of Wwox-sufficient MCF7 cells. Intratumoral Wwox restoration, through Ad-WWOX infection or endogenous Wwox reactivation by 5-aza-2'-deoxycytidine injection, suppressed tumor growth in nude mice by inducing apoptosis. Alteration of global methylation levels was not observed.


CONCLUSIONS
The results confirm that overexpression of exogenous Wwox inhibits breast cancer cell growth in vitro and in vivo and, perhaps more importantly, shows that restoration of endogenous Wwox expression, and likely other proteins, by treatment with a de novo methyltransferase inhibitor, also inhibits breast cancer cell growth and reverses breast cancer xenograft growth.
Iliopoulos
Dimitrios
D
Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Fabbri
Muller
M
Druck
Teresa
T
Qin
Haiyan R
HR
Han
Shuang-Yin
SY
Huebner
Kay
K
D000256:Adenoviridae / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D018076:DNA, Complementary / Q000378:metabolism; D000077209:Decitabine; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D009363:Neoplasm Proteins / Q000737:chemistry; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000502:physiology*; D034622:RNA Interference; D013997:Time Factors; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; D001374:Azacitidine