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HOXA5 Acts Directly Downstream of Retinoic Acid Receptor B and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition

Abstract
The promise of retinoids as chemopreventive agents in breastcancer is based on the differentiation and apoptosis inducedupon their binding to the retinoic acid (RA) receptor B (RARB).
We have previously shown that HOXA5induces apoptosis inbreast cancer cells. In this study, we investigated whether RA/RARB and HOXA5actions intersect to induce apoptosis anddifferentiation in breast cancer cells. We found that HOXA5expression can be induced by RA only in RARB-positive breast
cancer cells. We have, for the first time, identified the RAresponse element in HOXA5, which was found to be located inthe 3¶ end of the gene. Chromatin immunoprecipitation assaysshowed that RARB binds directly to this region in vivo.
Overexpression of RARb strongly enhances RA responsiveness,and knocking down RARb expression abolishes RA-mediated
induction of HOXA5expre ssion in breast cancer cells. Inaddition, there is coordinated loss of both HOXA5 and RARb
expression during neoplastic transformation and progressionin the breast epithelial cell model, MCF10A. Knockdown ofHOXA5expre ssion partially abrogates retinoid-induced apoptosis
and promotes cell survival upon RA treatment. Theseresults strongly suggest that HOXA5acts directly downstreamof RARb and may contribute to retinoid-induced anticancerand chemopreventive effects. [Cancer Res 2007;67(17):8007–13]
Introduction
Retinoids, the natural and synthetic derivatives of vitamin A,
exert profound effects on cell growth, differentiation, apoptosis,and morphogenesis (1). They are currently used in the treatment ofepithelial cancer and promyelocytic leukemia and are being
evaluated as preventive and therapeutic agents for a variety ofhuman cancers, including breast cancer (2–4). The effects ofretinoids are mainly mediated by two classes of nuclear receptors,
the retinoic acid (RA) receptors (RAR) and retinoid X receptors(RXR; refs. 1, 5). 9-Cis-RA is a high-affinity natural ligand for both
RARs and RXRs (6), whereas all-trans-RA is a high-affinity naturalligand only for the RARs (7). RARs and RXRs are each encoded bythree distinct genes (a, b, c), which function as ligand-activated
transcription factors (1). RARs interact with RXRs, forming RXRRARheterodimers that bind to RA response elements (RARE) tocontrol the expression of RA-responsive genes in the presence of
retinoids (1). Some of the target genes are RARs themselves, inparticular the RARb gene, for which a RARE (hRARE) wasidentified in the promoter region (8).
Altered nuclear receptor activities are associated with carcinogenesis.
In particular, loss of RARb expression was found in anumber of malignancies, including carcinomas of lung and breast,and squamous cell carcinomas of the head and neck (9–11). A
growing body of literature has shown that the anticancer effect of
RA is primarily mediated by RARh, which is a potent tumorsuppressorprotein (12, 13). For example, inhibition of RARbexpression in RARb-positive cancer cells abolished the RA-inducedapoptotic effect (14). Conversely, reexpression of RARb in RARbnegativeancer cells restored RA-induced growth inhibition,apoptosis, and decreased tumorigenicity (12, 15). In phase I/IIclinical trials of breast cancer testing a combination of all-trans-RA
and tamoxifen, RARh expression was found to be consisten本论文由英语论文网提供整理，提供论文代写，英语论文代写，代写论文，代写英语论文，代写留学生论文，代写英文论文，留学生论文代写相关核心关键词搜索。