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tlyelevated in the breast tissue (16). However, how RARh exerts its
anticancer activity is still largely unknown.
HOX gene expression is regulated by RA in embryonic cells and
tissues (17). In vertebrates, there are 39 HOX genes that are
organized into four clusters (i.e., HOXA, HOXB, HOXC, and HOXD;
ref. 18). In embryonic carcinoma cells, expression of the entire
HOXB gene cluster can be induced by RA treatment (19). In
contrast, in differentiated cells and tumor cells, very few HOX
genes can be induced by RA (20). Despite efforts to identify the
RAREs for HOX genes, only five RAREs have been identified for
5 of 39 HOX genes (HOXA1, HOXB1, HOXA4, HOXB4, and HOXD4;
refs. 21–24). HOXA5 expression has been shown to be regulated by
RA in embryonic carcinoma cells and in developing mouse lung
(25, 26). No RARE has yet been identified for HOXA5. How HOXA5
expression is regulated by RA and the role of HOX gene in RAmediated
cellular function is poorly understood.
Recently, our laboratory has shown that HOXA5 expression is
lost in >60% breast cancer cell lines and primary tumors (27, 28).
Overexpression of HOXA5 in breast cancer cells induced apoptosis
(27, 29). To determine if HOXA5 expression can be reactivated by
RA, we treated a variety of breast cancer cells with RA and its
analogues. We found that HOXA5 expression can be induced only
in RARb-positive breast cancer cells. Further, we identified the
RARE to which RARh binds directly. We also showed that
induction of HOXA5 is important for RA-mediated apoptosis and
cellular growth inhibition. This study suggested that HOXA5 acts
directly downstream of RARb and plays an important role in RAmediated
anticancer activity.
Materials and Methods
Reagents and cell culture. All of the retinoids (all-trans-RA, 9-cis-RA,
13-cis -RA, and 4-HPR) were purchased from Sigma-Aldrich. RARh
Requests for reprints: Saraswati Sukumar, Johns Hopkins University School of
Medicine, 1650 Orleans Street, CRB-IRoom 143, Baltimore, MD 21231-1000. Phone:
410-614-2479; Fax: 410-614-4073; E-mail: saras@jhmi.edu.
I2007 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-07-1405
www.aacrjournals.org 8007 Cancer Res 2007; 67: (17). September 1, 2007
Research Article

 

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