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Bcl-XLExpression and Its Downregulation by a Novel Retinoid in Breast Carcinoma Cells

Abstract We have recently found a novel retinoid, 6-[3-(1-adamantyl)-4-hydroxphenyl]-2-naphthalene carboxylic acid (CD437), which induces G 1 cell cycle arrest and apoptosis in human breast carcinoma (HBC) cells ( Oncogene 11, 493–504, 1995). CD437 downregulates the expression of a number of proteins which antagonize apoptosis. bcl-X L , a homologue of bcl-2, antagonizes apoptosis, while bcl-X S enhances apoptosis. We have found that estrogen receptor (ER)-negative HBCs express higher levels of bcl-X L and significantly lower levels of bcl-2 than their ER-positive counterparts. Neither cell type expresses bcl-X S . The addition of CD437 (1 μ M ) results in a fourfold downregulation of bcl-X L mRNA and protein levels followed by apoptosis in MDA-MB-231 and MDA-MB-468 cells. CD437 concentrations as low as 10 n M cause a significant reduction in both bcl-X mRNA and bcl-X L protein expression. CD437-dependent downregulation of bcl-X mRNA and bcl-X L protein expression occurs within 24 h of CD437 addition to the cells. Retinoic acid does not effect bcl-X mRNA or bcl-X L protein expression. CD437 is a potent inducer of apoptosis in a number of breast carcinoma cells lines and downregulates the expression of a number of proteins which antagonize apoptosis.