Search

Abstract: Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-κB), which is a major component in cancer cell invasion. The present study investigated whether DHAvD can modulate MMP-9 expression and cell invasion in MCF-7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-κB and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been identified as a potential source of therapy for human cancers. However, PPARγ ligands have a limitation for breast cancer therapy, since estrogen receptor α (ERα) negatively interferes with PPARγ signaling in breast cancer cells. Here we show that ERα inhihits PPARγ transactivity and ERα-mediated inhibition of PPARγ transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ERα with 17-β-estradiol blocked PPRE transactivity induced by troglitazone, a PPARγ ligand, indicating the resistance of ERα-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ERα-negative MDA-MB-231 cells more than that of ERα-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ERα-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ERα-positive MCF-7 cells. [Copyright &y& Elsevier]

Abstract: Estrogen stimulates cell proliferation in breast cancer. The biological effects of estrogen are mediated through two intracellular receptors, estrogen receptor-α (ERα) and estrogen receptor-β (ERβ). However, the role of ERs in the proliferative action of estrogen is not well established. Recently, it has been known that ER activates phosphatidylinositol-3-OH kinase (PI3K) through binding with the p85 regulatory subunit of PI3K. Therefore, possible mechanisms may include ER-mediated phosphoinositide metabolism with subsequent formation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is generated from phosphatidylinositol 4,5-bisphosphate via PI3K activation. The present study demonstrates that 17β-estradiol (E2) up-regulates PI3K in an ERα-dependent manner, but not ERβ, and stimulates cell growth in breast cancer cells. In order to study this phenomenon, we have treated ERα-positive MCF-7 cells and ERα-negative MDA-MB-231 cells with 10nM E2. Treatment of MCF-7 cells with E2 resulted in a marked increase in PI3K (p85) expression, which paralleled an increase in phospho-Akt (Ser-473) and PIP3 level. These observations also correlated with an increased activity to E2-induced cell proliferation. However, these effects of E2 on breast cancer cells were not observed in the MDA-MB-231 cell line, indicating that the E2-mediated up-regulation of PI3K/Akt pathway is ERα-dependent. These results suggest that estrogen activates PI3K/Akt signaling through ERα-dependent mechanism in MCF-7 cells. [Copyright &y& Elsevier]