Rich66
01-15-2010, 11:06 PM
Carcinogenesis. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Carcinogene sis.%27%29;) 2010 Jan 12. [Epub ahead of print]
Genistein Induces Enhanced Growth Promotion in ER Positive/erbB-2 Overexpressing Breast Cancers by ER-erbB-2 crosstalk and p27/kip1 Downregulation.
Yang X (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yang%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yang S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yang%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), McKimmey C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22McKimmey%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Liu B (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Liu%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Edgerton S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Edgerton%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Bales W (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bales%20W%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Archer L (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Archer%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Thor AD (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Thor%20AD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pathology, University of Oklahoma Health Sciences Center.
Genistein is a major 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 and noted in approximately 10-20% 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 to 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 MAPK/Erk. Blockade of the PI3K 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 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. The underlying mechanisms involve enhanced ER-erbB-2 crosstalk and p27/kip1 downregulation.
PMID: 20067990 [PubMed - as supplied by publisher]
Genistein Induces Enhanced Growth Promotion in ER Positive/erbB-2 Overexpressing Breast Cancers by ER-erbB-2 crosstalk and p27/kip1 Downregulation.
Yang X (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yang%20X%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yang S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yang%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), McKimmey C (http://www.ncbi.nlm.nih.gov/pubmed?term=%22McKimmey%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Liu B (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Liu%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Edgerton S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Edgerton%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Bales W (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Bales%20W%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Archer L (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Archer%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Thor AD (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Thor%20AD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pathology, University of Oklahoma Health Sciences Center.
Genistein is a major 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 and noted in approximately 10-20% 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 to 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 MAPK/Erk. Blockade of the PI3K 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 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. The underlying mechanisms involve enhanced ER-erbB-2 crosstalk and p27/kip1 downregulation.
PMID: 20067990 [PubMed - as supplied by publisher]