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Targeting HER-2/neu-overexpressing breast cancer cells by an antisense iron responsive element-directed gene expression.

Abstract：

:Overexpression of HER-2/neu proto-oncogene is found in many human cancers including 20-30% of breast cancer and is a predictor of poor prognosis. To target breast cancer cells that overexpress HER-2/neu mRNA, we previously described a novel strategy that combines the principle of antisense (AS) and translational inhibitory activity conferred by an iron-responsive element (IRE) (AS-IRE). Here, we showed that three potential AS-IREs, i.e. AS-IRE1, 4, and 5, derived from HER-2/neu antisense sequence could bind endogenous iron regulatory protein (IRP) and, when placed in 5' untranslated region (5'UTR) of a reporter gene, the gene expression could be translationally repressed by recombinant IRP in vitro. Using AS-IRE4 as our model, we demonstrated that it is regulated by iron, and importantly, such regulation is impaired in HER-2/neu-overexpressing breast cancer cells. Furthermore, we showed that AS-IRE4 could preferentially direct the expression of a reporter gene in HER-2/neu-overexpressing breast cancer cells. Interestingly, when AS-IRE4 was placed in 5'UTR of Bax gene, a pro-apoptotic protein in the Bcl-2 protein family, we observed a preferential cell killing in breast cancer cells that overexpress HER-2/neu. Taken together, our results suggest that AS-IRE behaves as a functional IRE and it may direct therapeutic gene expression to preferentially target HER-2/neu-overexpressing breast cancer cells.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Li Z,Xia W,Fang B,Yan DH

doi

10.1016/s0304-3835(01)00700-5

keywords:

subject

Has Abstract

pub_date

2001-12-28 00:00:00

pages

151-8

issue

2

eissn

0304-3835

issn

1872-7980

pii

S0304383501007005

journal_volume

174

pub_type

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