Abstract:
:Genistein is a major isoflavone with known hormonal and tyrosine kinase-modulating activities. Genistein has been shown to promote the growth of estrogen receptor positive (ER+) MCF-7 cells. In ER-negative (ER-)/erbB-2-overexpressing (erbB-2+) cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER+/erbB-2-altered breast cancers (known as luminal type B and noted in approximately 10 to 20% of breast cancers) have not been well explored. Using erbB-2-transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared with control MCF-7 cells. These responses were accompanied by increased phosphorylation of ERalpha and ER signaling, without increase in ER protein levels. Genistein-treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase. Blockade of the phosphatidylinositol 3-kinase and/or MAPK pathways abrogated genistein-induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein-treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein-mediated growth promotion. In aggregate, our data suggest that the concomitant coexpression of ER and erbB-2 makes breast cancers particularly susceptible to the growth-promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER-erbB-2 cross talk and p27/kip1 downregulation.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Yang X,Yang S,McKimmey C,Liu B,Edgerton SM,Bales W,Archer LT,Thor ADdoi
10.1093/carcin/bgq007subject
Has Abstractpub_date
2010-04-01 00:00:00pages
695-702issue
4eissn
0143-3334issn
1460-2180pii
bgq007journal_volume
31pub_type
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