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Nutrition and Cancer

Excentric Cleavage Products of ß-Carotene Inhibit Estrogen Receptor Positive and Negative Breast Tumor Cell Growth In Vitro and Inhibit Activator Protein-1-Mediated Transcriptional Activation¹

Elmi C. Tibaduiza^*, James C. Fleet, Robert M. Russell^** and Norman I. Krinsky^**,2

^* Molecular Pharmacology Research Center at the New England Medical Center, Boston, MA 02111; Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47906; ^** Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; and the Department of Biochemistry, School of Medicine, Tufts University, Boston, MA 02111

²To whom correspondence should be addressed. E-mail: norman.krinsky{at}tufts.edu

Both retinoids and carotenoids are potentially useful chemopreventive agents. In this study we tested the effect of synthetic excentric cleavage products of ß-carotene on the growth of the MCF-7, Hs578T and MDA-MB-231 human breast cancer cells. The apo-ß-carotenoic acids (ß-apo-CA) ß-apo-14'-, ß-apo-12'-, ß-apo-10'- and ß-apo-8'-CA are structurally similar to all-trans-retinoic acid (atRA) but have different side chain lengths. Nine days of treatment with atRA inhibited MCF-7 and Hs578T cell proliferation in a dose-dependent manner. ß-apo-14'-CA and ß-apo-12'-CA significantly inhibited MCF-7 growth, whereas only ß-apo-14'-CA inhibited Hs578T growth. None of these treatments inhibited the growth of MDA-MB-231 cells. Potential mechanisms of growth inhibition, i.e., regulation of the cell cycle control proteins E2F1 and retinoblastoma protein (RB), and effect on activator protein-1 (AP-1)-mediated gene regulation were examined. ß-apo-14'-CA and atRA inhibited the expression of E2F1 protein in MCF-7 and Hs578T cells. ß-apo-14'-CA, ß-apo-12'-CA and atRA down-regulated RB protein expression in MCF-7 but not in Hs578T cells. The effect of phorbol ester-induced transcriptional activation of a collagenase promoter-reporter gene construct was strongly inhibited by 1 µmol/L ß-apo-14'-CA, atRA (MCF-7, Hs578T) or ß-apo-12'-CA (MCF-7). These effects were due neither to cellular conversion of ß-apo-CA to atRA nor to high affinity binding to the retinoid acid receptors. Thus, ß-apo-CAs were effective inhibitors of breast tumor cell proliferation, possibly mediated through down-regulation of cell cycle regulatory proteins and/or inhibition of AP-1 transcriptional activity. The ability of ß-apo-CA to regulate breast tumor cell growth independently of conversion to atRA suggests that these compounds may have fewer side effects than retinoids and, therefore, have a potential chemotherapeutic value that deserves further examination.

KEY WORDS: • ß-carotene • excentric cleavage • breast tumor cells • activator protein-1 • retinoblastoma protein • E2F1

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