Log rank Mantel Cox tests demon strated that a decrease in CTCs after treatment

Indeed, several CREB target genes including oncogenes involved in RAS and JUN activation and inhibition of CDKNB1 p27 Kip1 and p53 activity, an anti apoptotic protein, オーダー ARQ 197 and a membrane receptor signal regulator were increased after EGF stimulation. Another pathway that is activated after EGF stimula tion is STAT3 mediated signalling. Stat3 can be activated through EGFR signalling, but signalling through this pathway may also be increased because expression of both this transcription factor itself and its upstream activator, IL20 are increased after EGF stimulation. In addition, the receptor components IL6R, OSMR, GP130 and the ligand LIF are also increased which may lead to STAT3 activation through JAK2.<br><br> Also after EGF stimulation, there is a down regulation of pro apoptosis factors and a tumor suppressor, and up regulation of anti apoptotic factors, which may contribute to cell proliferation and survival. Discussion Resistance to endocrine therapy in breast cancer remains a major problem purchase AZD0530 in the clinic. The mechanism behind this resistance is complex and it is still unclear whether tamoxifen resistance is based on 1 decreased transcrip tion inhibition and consequent proliferation inhibition, 2 decreased proliferation inhibition via non classical genomic or non genomic actions of the ER, or 3 ER independent mechanisms. Here we studied the role of EGFR signalling in this process, using estrogen responsive MCF7 cells that have increased expression of wild type EGFR. We showed that EGF driven signalling in these cells is sufficient to maintain ER independent cell proliferation.<br><br> We generated a MCF7 cell line with ectopic expression of EGFR, Alvocidib 臨床試験 which allowed the unbiased analysis of the inter action of EGFR and ER signalling. In contrast, in many studies on the mechanism of tamoxifen resistance, MCF7 cells are used that already have an increased expression or constitutive activation of EGFR and or downstream MAPK or Akt activation due to long term culture in the presence of tamoxifen. This prohibits the investigation of the intrinsic effect of EGFR signalling on the antagonistic activity of tamoxifen in cells that, in the absence of EGF, respond similarly as the parental MCF7 cells. With respect to ER expression, this was similar in our MCF7 EGFR and parent MCF7 cells, and resembles tamoxifen resistant ER positive human tumours that express ER at normal levels.<br><br> Therefore, our MCF7 EGFR cell line represents an important tool to study the mechanisms of tamoxifen resistance in a more clinically relevant model. Ectopic expression of human EGFR in MCF7 cells induced cell proliferation upon stimulation with EGF, which was ER independent, since ER knock down did not affect EGF induced proliferation. In agreement with this, EGF induced proliferation was not blocked by tamoxifen or fulvestrant. Therefore, increased EGFR expression in ER positive breast cancers may be a sole important determinant for prediction of anti estrogen resistance. Although our data are consistent with litera ture data showing tamoxifen, and also fulvestrant resistance upon increased EGFR expression in breast cancer cells, typically these studies involved human breast cancer cell lines that were long term cultured in the pres ence of these antagonists.