Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P31749 (AKT)
22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation. Unexpectedly, activation of two key Ras effector pathways, the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT signaling pathways, was not always associated with Ras activation. Ras activation also did not correlate with invasion or the expression of proteins associated with tumor cell invasion (estrogen receptor alpha and cyclooxygenase 2). We then examined the role of Ras signaling in mediating resistance to matrix deprivation-induced apoptosis (anoikis). Surprisingly, we found that ERK and phosphatidylinositol 3'-kinase/AKT activation did not have significant roles in conferring anoikis resistance. Taken together, these observations show that Ras signaling exhibits significant cell context variations and that other effector pathways may be important for Ras-mediated oncogenesis, as well as for anoikis resistance, in breast cancer. Additionally, because ERK and AKT activation are not strictly associated with Ras activation, pharmacological inhibitors of these two signaling pathways may not be the best approach for inhibition of aberrant Ras function in breast cancer treatment.
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PMID:Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. 1523 70

A fraction of the nuclear estrogen receptor alpha (ERalpha) is localized to the plasma membrane region of 17beta-estradiol (E2) target cells. We previously reported that ERalpha is a palmitoylated protein. To gain insight into the molecular mechanism of ERalpha residence at the plasma membrane, we tested both the role of palmitoylation and the impact of E2 stimulation on ERalpha membrane localization. The cancer cell lines expressing transfected or endogenous human ERalpha (HeLa and HepG2, respectively) or the ERalpha nonpalmitoylable Cys447Ala mutant transfected in HeLa cells were used as experimental models. We found that palmitoylation of ERalpha enacts ERalpha association with the plasma membrane, interaction with the membrane protein caveolin-1, and nongenomic activities, including activation of signaling pathways and cell proliferation (i.e., ERK and AKT activation, cyclin D1 promoter activity, DNA synthesis). Moreover, E2 reduces both ERalpha palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner. These data point to the physiological role of ERalpha palmitoylation in the receptor localization to the cell membrane and in the regulation of the E2-induced cell proliferation.
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PMID:Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. 1549 58

The growth of both normal and transformed epithelial cells of the female reproductive system is stimulated by estrogens, mainly through the activation of estrogen receptor alpha (ERalpha), which is a ligand-regulated transcription factor. The selective ER modulator tamoxifen (TAM) has been widely used as an ER antagonist in breast tumor; however, long-term treatment is associated with an increased risk of endometrial cancer. To provide new insights into the potential mechanisms involved in the agonistic activity exerted by TAM in the uterus, we evaluated the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, to transactivate wild-type ERalpha and its splice variant expressed in Ishikawa and HEC1A endometrial tumor cells, respectively. OHT was able to antagonize only the activation of ERalpha by 17beta-estradiol (E2) in Ishikawa cells, whereas it up-regulated c-fos expression in a rapid manner similar to E2 and independently of ERalpha in both cell lines. This stimulation occurred through the G protein-coupled receptor named GPR30 and required Src-related and epidermal growth factor receptor tyrosine kinase activities, along with the activation of both ERK1/2 and phosphatidylinositol 3-kinase/AKT pathways. Most importantly, OHT, like E2, stimulated the proliferation of Ishikawa as well as HEC1A cells. Transfecting a GPR30 antisense expression vector in both endometrial cancer cell lines, OHT was no longer able to induce growth effects, whereas the proliferative response to E2 was completely abrogated only in HEC1A cells. Furthermore, in the presence of the inhibitors of MAPK and phosphatidylinositol 3-kinase pathways, PD 98059 and wortmannin, respectively, E2 and OHT did not elicit growth stimulation. Our data demonstrate a new mode of action of E2 and OHT in endometrial cancer cells, contributing to a better understanding of the molecular mechanisms involved in their uterine agonistic activity.
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PMID:The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. 1623 58

Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor beta, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor alpha compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients.
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PMID:Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. 1845 Nov 80

Estrogen regulates several biological processes through estrogen receptor alpha (ERalpha) and ERbeta. ERalpha-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERalpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERalpha binding sites, respectively, with approximately 60% overlap. In both cell types, approximately 40% of estrogen-regulated genes associate with ERalpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappaB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERalpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERalpha binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERalpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERalpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.
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PMID:AKT alters genome-wide estrogen receptor alpha binding and impacts estrogen signaling in breast cancer. 1883 36

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPARgamma in tumorigenesis, transgenic mice were generated with mammary gland-directed expression of the dominant-negative transgene Pax8PPARgamma. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epithelial cells expressed a greater percentage of CD29(hi)/CD24(neg), CK5(+), and double-positive CK14/CK18 cells. These changes correlated with reduced PTEN and increased Ras and extracellular signal-regulated kinase (ERK) and AKT activation. Although spontaneous tumorigenesis did not occur, transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis, which in contrast to WT mice resulted in a high tumor multiplicity and, most importantly, in the appearance of predominantly estrogen receptor alpha-positive (ER(+)) ductal adenocarcinomas. Tumors expressed a similar PTEN(lo)/pERK(hi)/pAKT(hi) phenotype as mammary epithelium and exhibited high activation of estrogen response element-dependent reporter gene activity. Tumorigenesis in MMTV-Pax8PPARgamma mice was insensitive to the chemopreventive effect of a PPARgamma agonist but was profoundly inhibited by the ER antagonist fulvestrant. These results reveal important new insights into the previously unrecognized role of PPARgamma in the specification of mammary lineage and the development of ER(+) tumors.
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PMID:Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification. 1914 85

The flavonol quercetin, especially abundant in apple, wine, and onions, is reported to have anti-proliferative effects in many cancer cell lines. Antioxidant or pro-oxidant activities and kinase inhibition have been proposed as molecular mechanisms for these effects. In addition, an estrogenic activity has been observed but, at the present, it is poorly understood whether this latter activity plays a role in the quercetin-induced anti-proliferative effects. Here, we studied the molecular mechanisms of quercetin committed to the generation of an apoptotic cascade in cancer cells devoid or containing transfected estrogen receptor alpha (ERalpha; i.e., human cervix epitheloid carcinoma HeLa cells). Although none of tested quercetin concentrations increase reactive oxygen species (ROS) generation in HeLa cells, quercetin stimulation prevents the H(2)O(2)-induced ROS production both in the presence and in the absence of ERalpha. However, this flavonoid induces the activation of p38/MAPK, leading to the pro-apoptotic caspase-3 activation and to the poly(ADP-ribose) polymerase cleavage only in the presence of ERalpha. Notably, no down-regulation of survival kinases (i.e., AKT and ERK) was reported. Taken together, these findings suggest that quercetin results in HeLa cell death through an ERalpha-dependent mechanism involving caspase- and p38 kinase activation. These findings indicate new potential chemopreventive actions of flavonoids on cancer growth.
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PMID:Quercetin-induced apoptotic cascade in cancer cells: antioxidant versus estrogen receptor alpha-dependent mechanisms. 1919 71

We have previously shown that 17beta-estradiol (E(2)) increases vascular endothelial growth factor A (Vegfa) gene expression in the rat uterus, resulting in increased microvascular permeability, and that this involves the simultaneous recruitment of hypoxia-inducible factor 1 (HIF1) and estrogen receptor alpha (ESR1) to the Vegfa gene promoter. Both events require the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. However, those studies were carried out using whole uterine tissue, and while most evidence indicates that the likely site of E(2)-induced Vegfa expression is luminal epithelial (LE) cells, other studies have identified stromal cells as the site of that expression. To address this question, the pathway regulating Vegfa expression was reexamined using LE cells rapidly isolated after E(2) treatment. In addition, we further characterized the nature of the receptor through which E(2) triggers the signaling events that lead to Vegfa expression using the specific ESR1 antagonist ICI 182,780. In agreement with previous results in the whole uterus, E(2) stimulated Vegfa mRNA expression in LE cells, peaking at 1 h (4- to 14-fold) and returning to basal levels by 4 h. Treatment with E(2) also increased phosphorylation of AKT in LE cells, as well as of the downstream mediators FRAP1 (mTOR), GSK3B, and MDM2. The alpha subunit of HIF1 (HIF1A) was present in LE cells before E(2) treatment, was unchanged 1 h after E(2), but was >2-fold higher by 4 h. Chromatin immunoprecipitation analysis showed that HIF1A was recruited to the Vegfa promoter by 1 h and was absent again by 4 h. The E(2) activation of the PI3K/AKT pathway, HIF1A recruitment to the Vegfa promoter, and Vegfa expression were all blocked by ICI 182,780. In summary, the rapid E(2)-induced signaling events that lead to the expression of Vegfa observed previously using the whole uterus occur in LE cells and appear to be initiated via a membrane form of ESR1.
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PMID:Estrogen rapidly activates the PI3K/AKT pathway and hypoxia-inducible factor 1 and induces vascular endothelial growth factor A expression in luminal epithelial cells of the rat uterus. 1942 Mar 88

Estradiol (E2) regulates gene expression at the transcriptional level by functioning as a ligand for estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). E2-inducible proteins c-Myc and E2Fs are required for optimal ERalpha activity and secondary estrogen responses, respectively. We show that E2 induces 21 microRNAs and represses seven microRNAs in MCF-7 breast cancer cells; these microRNAs have the potential to control 420 E2-regulated and 757 non-E2-regulated mRNAs at the post-transcriptional level. The serine/threonine kinase, AKT, alters E2-regulated expression of microRNAs. E2 induced the expression of eight Let-7 family members, miR-98 and miR-21 microRNAs; these microRNAs reduced the levels of c-Myc and E2F2 proteins. Dicer, a ribonuclease III enzyme required for microRNA processing, is also an E2-inducible gene. Several E2-regulated microRNA genes are associated with ERalpha-binding sites or located in the intragenic region of estrogen-regulated genes. We propose that the clinical course of ERalpha-positive breast cancers is dependent on the balance between E2-regulated tumor-suppressor microRNAs and oncogenic microRNAs. Additionally, our studies reveal a negative-regulatory loop controlling E2 response through microRNAs as well as differences in E2-induced transcriptome and proteome.
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PMID:Estradiol-regulated microRNAs control estradiol response in breast cancer cells. 1952 81

Aromatase inhibitors are important drugs to treat estrogen receptor alpha (ERalpha)-positive postmenopausal breast cancer patients. However, development of resistance to aromatase inhibitors has been observed. We examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of aromatase inhibitor-resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. Aromatase inhibitor-responsive MCF-7aro and aromatase inhibitor-resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G(2) cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERalpha, the ERalpha transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Collectively, results from this study provide data to support that HSP90 inhibitors may be an effective therapy to treat aromatase inhibitor-resistant breast cancers and that improved efficacy can be achieved by combined use of a HSP90 inhibitor and an AKT inhibitor.
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PMID:Heat shock protein 90 inhibitors: new mode of therapy to overcome endocrine resistance. 1986 37


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