Excentric cleavage products of β-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation

Abstract

Both retinoids and carotenoids are potentially useful chemopreventive agents. In this study we tested the effect of synthetic excentric cleavage products of β-carotene on the growth of the MCF-7, Hs578T and MDA-MB-231 human breast cancer cells. The apo-β-carotenoic acids (β-apo-CA) β-apo-14′-, β-apo-12′-, β-apo10′- and β-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. β-apo-14′-CA and β-apo-12′-CA significantly inhibited MCF-7 growth, whereas only β-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. β-apo-14′-CA and atRA inhibited the expression of E2F1 protein in MCF-7 and Hs578T cells. β-apo-14′-CA, β-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 β-apo-14′-CA, atRA (MCF-7, Hs578) or β-apo-14′-CA (MCF-7). These effects were due neither to cellular conversion of β-apo-CA to atRA nor to high affinity binding to the retinoid acid receptors. Thus, β-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 β-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.