Abstract
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. 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. 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. 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.
Highlights
The WWOX gene is down-regulated in breast cancer and loss of Wwox expression correlates with important clinical features of breast cancer
To investigate tumor suppression in breast cancer, we have examined the in vitro and in vivo effects of Wwox protein expression in breast cancer cells with high (MCF7), low (BT-474), or no (MDA-MB-231 and HCC1937) endogenous Wwox expression, by adenovirus carrying WWOX cDNA (Ad-WWOX) infection or by endogenous Wwox reactivation
Cells were transduced with Ad-WWOX or Ad-green fluorescent protein (GFP) at appropriate multiplicities of infection (MOI), and transduction efficiency was assessed by visualization of GFPexpressing cells
Summary
The WWOX gene is down-regulated in breast cancer and loss of Wwox expression correlates with important clinical features of breast cancer. We have examined the effect of restoration of Wwox expression in breast cancer-derived cells. Experimental Design: 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. Esophageal squamous cell carcinoma, non – small cell lung cancer, and breast cancer showed a high loss of heterozygosity rate, low mutation rate, and expression of aberrant transcripts of the WWOX gene To investigate tumor suppression in breast cancer, we have examined the in vitro and in vivo effects of Wwox protein expression in breast cancer cells with high (MCF7), low (BT-474), or no (MDA-MB-231 and HCC1937) endogenous Wwox expression, by Ad-WWOX infection or by endogenous Wwox reactivation
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