Genistein is a major plant-derived isoflavone with known hormonal and tyrosine kinase modulating activities. Genistein has been shown to promote the growth of estrogen receptor (ER) positive MCF-7 cells. In ER negative/erbB-2 overexpressing 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 positive/erbB-2 altered breast cancers (known as luminal type B, 10-20% of invasive ductal breast cancers) have not been well explored. This study focuses on the effect of genistein on breast cancer cells with different ER and erbB-2 status. Using erbB-2 transfected ER+ MCF-7 cells, we found that genistein induced enhanced-cellular-proliferation and tamoxifen resistance as compared to control MCF-7 cells. In contrast, genistein associated growth promotion was not observed in erbB-2 overexpressing/ER- MDA-MB-435 cells. Our data indicate that genistein mediated-enhanced growth promotion of MCF-7/erbB-2 cells was accompanied by increased phosphorylation of ERα and ER signaling, without increases in ER protein levels. Genistein treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and MAPK/Erk. Blockade of the PI3K and/or MAPK pathways abrogated genistein induced growth promotion, suggesting that genistein effects involve a crosstalk between the two 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, suggesting the role of p27 downregulation in genistein induced growth promotion. In aggregate, our data suggest that the concomitant co-expression of ER and erbB-2 makes breast cancers particularly susceptible to the growth promoting effects of genistein across a wide range of doses. Clinical studies to specifically evaluate the cancer promoting effects of dietary phytoestrogens on ER+, erbB-2+ (luminal type B) breast cancers, as compared to other cancer subtypes, is advised. Breast cancer patients with ER+/erbB-2+ tumors should be cautious when considering using soy-based products.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA