The majority of ER positive breast tumors overexpres sing 14 3 3 were of the luminal B subtype, tumors with a poorer outcome compared with luminal A. Consistent with this, comparative genomic inhibitor Erlotinib hybridization analyses have indicated that one of the most recurrent alterations in luminal B tumors is gain amplification of the 8q region that harbors 14 3 3. In addition to the prominent association of 14 3 3 with ER positive luminal B tumors, ca. 12% were basal breast cancers, another subtype with a poor prognosis. Collectively, our observations in primary breast Inhibitors,Modulators,Libraries tumors and in breast cancer cells in vitro provide evidence that the overex pression of 14 3 3 and the associated 14 3 3 gene sig nature identify a subgroup of ER positive tumors most likely to be resistant to endocrine therapies and to show early recurrence.

In addition, our studies reveal that 14 3 3 expression can also be increased as a consequence of tamoxifen treatment, and therefore, ironically, that tamoxifen itself, through upregulation of 14 3 3, may be contributing to the development Inhibitors,Modulators,Libraries of endocrine resistance. Broad impact of 14 3 3 on key cellular activities and signaling pathways 14 3 3 status had a great impact on cell signaling path ways and the molecular properties Inhibitors,Modulators,Libraries of breast cancer cells. With high 14 3 3, cells showed enhanced activation of EGFR, HER2, MAPK, and AKT, and increased ancho rage dependent and independent growth. These Inhibitors,Modulators,Libraries activ ities were suppressed by downregulation of 14 3 3.

Thus, 14 3 3 increases signaling through a variety of Inhibitors,Modulators,Libraries growth factor receptors and protein kinase pathways, stimulating a more robust and temporally prolonged activation of these pathways to promote survival and anti apoptotic signaling, and enhance the endocrine resistance of breast cancer cells. 14 3 3 is a member of a highly conserved family of 14 3 3 proteins, and it functions as a scaffold or plat form that regulates the activity and stability of interact ing proteins by binding to their phosphoserine and phosphothreonine motifs. It is noteworthy that 14 3 3 is the major form expressed in breast tumors and in ER positive breast cancer cells, and it was the only 14 3 3 isoform to show high upregulation by tamoxifen. The broad effects of 14 3 3 might indeed be expected for a scaffold adaptor protein that serves as a critical convergence factor in these signaling pathways, having known interactions with EGFR, HER2, and PKC, as well as additional signaling components such as RAF 1 and b catenin. Our observations now add regulation of FOXM1 as another important aspect of 14 3 3 activity in breast cancer http://www.selleckchem.com/products/MG132.html and endocrine resistance.