Feedback Regulation in Cancer

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exquisite sensitivity of the prostate gland androgenic steroids has provided support for the development of systemic therapy for prostate cancer for more than seventy godina.Stalni strategic approach that focused on inhibiting this unique signaling pathway led to the use of androgen-deprivation and antiandrogen therapy for cancer station Overview of advanced prostate cancer. These therapies and continue to serve as a standard of care, although, unfortunately, antiandrogen therapies are not curative, new approaches needed. With the advent of targeted therapies for cancer, antiandrogen agents have continued to form the foundation on which combination of therapies, including those aimed at the joint activity of oncogenic signals, can be developed.

In the case of prostate cancer, it has proved particularly challenging due to the extremely heterogeneous nature of the genetic changes that underlie this bolesti.Istaknuti molecular target for prostate cancer therapy is the PI3K-AKT signaling put.Nedavna study of 218 prostate cancer tumors showed that 42% of primary tumors and 100% metastases harbored genomic variation in the way.

best characterizes the genetic change in this time in PTEN, which has been shown to be mutated and / or show loss of heterozygosity in 15% of localized prostate cancer and 30% of metastatic disease. Small molecule inhibitors of PI3K-AKT signaling have been developed and tested clinically. Although the results of early clinical trials have been inconclusive, therapeutic activities PI3K-AKT inhibitor as an agent are generally been modest in patients with advanced prostate cancer. Thus, there is considerable effort to integrate rational PI3K-AKT inhibitors in combination therapy protocols.

In the last few issues of cancer cells, and report on cross Having identified the feedback regulation between AR and PTEN loss/PI3K-AKT signs of prostate cancer. Until the effective use of PB-Cre, Ptenlox / lox mouse model and carefully characterized human prostate cancer tissue samples, these two groups of investigators have original contribution to our understanding of the regulation of growth and survival signaling in prostate cancer cells and thereby to justify the use of a combination therapy for advanced prostate cancer. Using a similar experimental approach, the loss of PTEN function sets in motion a series of molecular events that establish a link between two expansive signaling networks that supervise the growth, survival and differentiation of prostate epithelial cells. Activation of PI3K-AKT signaling as a result of PTEN mutation in PB-Cre;. Ptenlox / lox mouse leads to suppression of AR signaling

In the last few issues of cancer cells, and report on cross Having identified the feedback regulation between AR and PTEN loss/PI3K-AKT signs of prostate cancer. Until the effective use of PB-Cre, Ptenlox / lox mouse model and carefully characterized human prostate cancer tissue samples, these two groups of investigators have original contribution to our understanding of the regulation of growth and survival signaling in prostate cancer cells and thereby to justify the use of a combination therapy for advanced prostate cancer. Using a similar experimental approach, the loss of PTEN function sets in motion a series of molecular events that establish a link between two expansive signaling networks that supervise the growth, survival and differentiation of prostate epithelial cells. Activation of PI3K-AKT signaling as a result of PTEN mutation in PB-Cre;. Ptenlox / lox mouse leads to suppression of AR signaling

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In the last few issues of cancer cells, and report on cross Having identified the feedback regulation between AR and PTEN loss/PI3K-AKT signs of prostate cancer. Until the effective use of PB-Cre, Ptenlox / lox mouse model and carefully characterized human prostate cancer tissue samples, these two groups of investigators have original contribution to our understanding of the regulation of growth and survival signaling in prostate cancer cells and thereby to justify the use of a combination therapy for advanced prostate cancer. Using a similar experimental approach, the loss of PTEN function sets in motion a series of molecular events that establish a link between two expansive signaling networks that supervise the growth, survival and differentiation of prostate epithelial cells. Activation of PI3K-AKT signaling as a result of PTEN mutation in PB-Cre;. Ptenlox / lox mouse leads to suppression of AR signaling

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Transcriptome analysis showed a significant overlap of up-and downregulated genes between intact male PTEN / mice and castrated wild-type mice and showed that PTEN loss is associated with reduced AR signaling in PTEN-deficiency of human prostate tumors. These results, together with those from previous studies show that loss of function of PTEN and activation of PI3K-AKT signaling plant the seeds for androgen-independent prostate cancer growth by establishing castrated genetic program. Using the pharmacologic and genetic approaches, different mechanisms contribute to the suppression of AR izlaz.PI3K-AKT, but not MEK signaling, is responsible for inhibiting AR signaling and that inhibition depends on the upstream HER kinase inhibition. Using PTEN re-expression of access, loss of PTEN can suppress androgen rapid gene through upregulation of Egr1 and C-jun transcriptional coregulators and the catalytic subunit of Polycomb repressive complex 2, Ezh2. Thus, PTEN loss may lead to repression of AR signaling at two levels: upstream suppression of MAPK kinase-stimulated her, and control / subversion AR-mediated transcription via increased expression of transcriptional coregulators and Histone methyltransferase. Probing the castration response PBCre; Ptenlox / lox mice, PB-myc mice and androgen-sensitive prostate cancer cells and analysis of double knockout mutant, PB-Cre, Ptenlox / smoked salmon, Arlox / Y, mouse and human prostate cancer specimens led to other key finding is surprising that the castration-or loss of AR increased AKT phosphorylation.

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A recent study indicates that TMPRSS2-ERG gene fusion product can interfere with androgen signaling in prostate cancer cells through multiple mechanisms, including binding to AR target genes and induction of EZH2 expression, which in turn can suppress prostate cell differentiation. In addition, under certain conditions, PI3K-AKT signaling can increase AR activity and induce AR target genes, such as p21WAF/CIP, which is associated with androgen-independent growth of prostate cancer. In light of new insights into this mechanistic framework that is the result of the discovery of mutual negative feedback connection of AR and PI3K-AKT signaling network, it May be possible to better characterize and delineate additional signaling pathways andidentifyadditional transcriptional coregulators and chromatin modifiers that the basis of specific target AR gene functions associated with androgen-dependent prostate growth and / or differentiation and androgen independent growth of cancer prostate.Neumoljiv selection process by which cancer cells develop resistance to all types of anticancer drugs is a research and clinical oncologistswith daunting task. Through their mutual discovery of an important negative feedback include AR and PTEN loss/PI3K-AKT signs of prostate cancer.

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