Estrogen and Myc negatively regulate expression of the EphA2 tyrosine kinase
ABSTRACT Estrogen receptor and c-Myc are frequently overexpressed during breast cancer progression but are downregulated in many aggressive forms of the disease. High levels of the EphA2 tyrosine kinase are consistently found in the most aggressive breast cancer cells, and EphA2 overexpression can increase metastatic potential. We demonstrate, herein, that estrogen and Myc negatively regulate EphA2 expression in mammary epithelial cells. These data reveal EphA2 as a downstream target of estrogen and Myc and suggest a mechanism by which estrogen and Myc may regulate breast cancer. J. Cell. Biochem. 85: 714–720, 2002. © 2002 Wiley-Liss, Inc.
Article: Effects of flavonoids genistein and biochanin a on gene expression and their metabolism in human mammary cells.[show abstract] [hide abstract]
ABSTRACT: Genistein (GEN) and biochanin A (BCA), dietary isoflavones, possess breast cancer-preventive properties. Our objective was to examine the effect of physiologically relevant concentrations of BCA and GEN on gene expression in normal (HMEC), immortalized but nontumorigenic (MCF12A), and tumorigenic (MCF7) mammary cells and to determine whether the differences in gene expression are related to differences in metabolism in the three types of mammary cells. Using cDNA arrays, we compared the gene expression after a 48-h incubation with 1 microM BCA, GEN, or vehicle. Treatment with GEN or BCA produced the greatest number of significant changes in HMEC compared with MCF12A or MCF7 cells. Unlike GEN, effects of BCA on gene expression were mostly beneficial, involving induction of tumor suppressor genes. Different extents of metabolism were observed in the three mammary cell types; however, GEN concentrations were very low following either GEN or BCA administration in all of the three cell types. Because there were only very low concentrations of GEN, compared with BCA concentrations, in HMEC and MCF12A cells treated with BCA and different gene expression changes were found after BCA and GEN treatment, these findings suggest that BCA has distinct effects compared with GEN. The results suggest that BCA may represent a better breast cancer-preventive agent than GEN.Nutrition and Cancer 02/2007; 57(1):48-58. · 2.78 Impact Factor
Article: Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines.[show abstract] [hide abstract]
ABSTRACT: Eph receptors are the largest family of receptor tyrosine kinases. Together with their ligands, the ephrins, they fulfill multiple biological functions. Aberrant expression of Ephs/ephrins leading to increased Eph receptor to ephrin ligand ratios is a critical factor in tumorigenesis, indicating that tight regulation of Eph and ephrin expression is essential for normal cell behavior. The 3'-untranslated regions (3'UTRs) of transcripts play an important yet widely underappreciated role in the control of protein expression. Based on the assumption that paralogues of large gene families might exhibit a conserved organization of regulatory elements in their 3'UTRs we applied a novel bioinformatics/molecular biology approach to the 3'UTR sequences of Eph/ephrin transcripts. We identified clusters of motifs consisting of cytoplasmic polyadenylation elements (CPEs), AU-rich elements (AREs) and HuR binding sites. These clusters bind multiple RNA-stabilizing and destabilizing factors, including HuR. Surprisingly, despite its widely accepted role as an mRNA-stabilizing protein, we further show that binding of HuR to these clusters actually destabilizes Eph/ephrin transcripts in tumor cell lines. Consequently, knockdown of HuR greatly modulates expression of multiple Ephs/ephrins at both the mRNA and protein levels. Together our studies suggest that overexpression of HuR as found in many progressive tumors could be causative for disarranged Eph receptor to ephrin ligand ratios leading to a higher degree of tissue invasiveness.PLoS ONE 01/2008; 3(7):e2780. · 4.09 Impact Factor
Article: Co-expression of estrogen receptor-alpha and targets of estrogen receptor action in proliferating monkey mammary epithelial cells.[show abstract] [hide abstract]
ABSTRACT: Failure to detect co-expression of estrogen receptor-alpha (ERalpha) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERalpha and Ki67 during the cell cycle could have been below detection limits. Immunohistochemistry was used on mammary tissue sections from estrogen treated rhesus monkeys to investigate co-expression of ERalpha and the proliferation antigen Ki67. Using the same methods, we investigated the cell localization of proteins involved in estrogen-induced proliferation, including cyclin D1, stromal cell-derived factor (SDF)-1, and MYC. ERalpha was co-expressed with the proliferation marker Ki67 as well as with SDF-1, MYC and cyclin D1 in mammary epithelial cells from estrogen-treated monkeys. ERalpha is expressed in proliferating mammary epithelial cells together with the estrogen-induced proteins MYC, cyclin D1 and SDF-1, consistent with a direct mitogenic action by estrogen in primate mammary epithelium.Breast cancer research: BCR 02/2006; 8(1):R10. · 5.24 Impact Factor