Flavonoid effects relevant to cancer.
Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17-beta estradiol (E2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human breast cancer cell lines. E2, genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells.
Brownson
Delia M
DM
Molecular Cell and Developmental Biology Section, The University of Texas at Austin, Austin, TX 78712, USA.
Azios
Nicolas G
NG
Fuqua
Brie K
BK
Dharmawardhane
Su F
SF
Mabry
Tom J
TJ
D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D010766:Phosphorylation; D048789:Phytoestrogens; D028321:Plant Preparations; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen / Q000032:analysis; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D013267:Stilbenes; D004958:Estradiol; C004742:daidzein; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol