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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor.
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PMID:Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. 1842 33

The androgen receptor (AR) is the most widely expressed steroid hormone receptor in human breast cancers and androgens including 5alpha-dihydrotestosterone are potent inhibitors of breast cancer cell proliferation. The extracellular signal-regulated mitogen activated protein kinase (ERK/MAPK) pathway is hyperactivated in a proportion of breast tumors and can interact with steroid hormone receptor signaling by altering receptor phosphorylation, turnover, ligand, and cofactor interactions. To examine the effects of ERK/ MAPK hyperactivity on AR levels, MCF-7 cells were stably transfected with a plasmid encoding a constitutively active MEK1 protein to create MCF-7-DeltaMEK1 cells. Treatment of MCF-7-DeltaMEK1 with androgens caused a transient increase in AR protein levels, similar to that observed in untransfected MCF-7 cells treated with androgens. Androgens also inhibited the proliferation of MCF-7-DeltaMEK1 cells by 50-60% following 8 days of treatment in association with increased accumulation of cells in the G1 phase of the cell cycle. These results indicate that although ERK/MAPK hyperactivation in breast cancer cells is associated with reduced estrogen receptor (ERalpha) levels and antiestrogen resistance, AR levels are maintained and breast cancer cells remain susceptible to the growth inhibitory effects of androgens.
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PMID:ERK/MAPK regulation of the androgen responsiveness of breast cancer cells. 1849 66

Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFkappaB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.
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PMID:Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate cancer. 1849 78

Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR). One subtype (molecular apocrine) has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.
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PMID:A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. 1851 91

PSA (prostate-specific antigen), a serine protease with chymotrypsin-like activity is the most useful tumor marker for prostate cancer screening, diagnosis, prognosis and monitoring. The identification of PSA in normal and tumoral mammary gland was regarded as a curiosity, but the confirmation of PSA expression in the mammary gland by others teams of researchers and the identification of specific mRNA in tumors with PSA immunoexpression initiated new perspectives for studies. The aim of this study was to examine the prevalence of PSA in breast cancers and to evaluate the correlations between PSA expression and some clinicopathological markers. We analyzed the expression of PSA in series of consecutive breast carcinomas by immunohistochemistry and correlated the PSA expression with the histological type and grade, nodal and metastasis status, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and HER2/neu expression. PSA expression was observed in 44.5% of breast cancers, particularly in lobular types of carcinoma (p<0.0001). In univariate analysis, the expression of PSA was statistically correlated with AR (p<0.0001), PR (p=0.01) and inversely correlated with HER2/neu overexpression (p=0.008) and G3 (p=0.02). PSA did not significantly correlate with ER expression, lymph node and metastasis status. In multivariate analysis, PR was a moderate predictor (p=0.024) but the lobular type (p=0.000), AR (p=0.000), HER2/neu (p=0.002) and G3 (p=0.008) were strong predictors for PSA immunoexpression.
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PMID:Prostate-specific antigen may serve as a pathological predictor in breast cancer. 1851 23

Previous studies have demonstrated that monospecific antisense oligonucleotides (oligos) directed against mRNA encoding proteins associated with tumor growth, death, and survival are efficacious against breast and prostate tumors. Targeted proteins, associated with different signal transduction pathways, have included transforming growth factor-alpha [TGF-alpha (MR(1))], its binding site the epidermal growth factor receptor [EGFR (MR(2))] sharing sequence homology to the breast cancer prognostic marker Her-2/neu, an apoptosis inhibiting protein [bcl-2 (MR(4))], and the androgen receptor [AR (MR(5))]. In attempts to enhance antisense therapy, recent reports describe how two of the binding sites mentioned above can be sequentially placed within a single complementary (bispecific) strand and administered either in the presence or absence of additional therapeutic agents. When tested against breast and prostate tumor cell lines specific differences were noted: MCF-7 breast cancer cells were more receptive to the inhibitory effects of monospecific oligos, whereas PC-3 and LNCaP prostate cells were particularly responsive to bispecifics. In an effort to identify agents which enhance the activity of oligos and which possess less toxicity than traditionally employed chemotherapeutics, Rapamycin, an immunosuppressive agent known to regulate tumor growth and signal transduction mediated by the mTOR receptor, is compared to paclitaxel in combination therapy employing monospecific or bispecific oligos. Bispecifics were constructed recognizing the binding sites for TGF-alpha and EGFR mRNA [TGF-alpha/EGFR (MR(12)) and EGFR/TGF-alpha (MR(21))]; another pair recognized binding sites for EGFR and bcl-2 [EGFR/bcl-2 (MR(24)) and bcl-2/EGFR (MR(42))]; while a third pair employed only against the LNCaP prostate cell line recognized bcl-2 and the androgen receptor [bcl-2/AR (MR4(45)) and AR/bcl-2 (MR(54))]. Oligo pairs differ in their 5'-3' linear binding site orientations, and were tested in vitro against MCF-7 breast and PC-3 and LNCaP prostate tumor cell lines. Following cell attachment, incubations were done for 2 days with the agents followed by 2 days in their absence. Five experiments evaluated the effect of monospecific or bispecific antisense oligos in combination with an LD(50) dosage of either Rapamycin or paclitaxel and led to the conclusion that although these agents act via different mechanisms, they are comparable in effectiveness.
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PMID:Multigene targeting of signal transduction pathways for the treatment of breast and prostate tumors: comparison between combination therapies employing bispecific oligonucleotides with either Rapamycin or Paclitaxel. 1868 47

In androgen sensitive LNCaP prostate cancer cells, the proliferation induced by the epidermal growth factor (EGF) involves a cross-talk between the EGF receptor (EGFR) and the androgen receptor (AR). In lung cancer the role of the EGF-EGFR transduction pathway has been documented, whereas androgen activity has received less attention. Here we demonstrate that in LNCaP and A549 non-small cell lung cancer (NSCLC), AR and EGFR are required for either 5alpha-dihydrotestosterone (DHT) or EGF-stimulated cell growth. Only EGF activated ERK signaling and up-regulated early gene expression, while DHT triggered the expression of classical AR-responsive genes with the exception of the EGF-induced PSA transcript in A549 cells. DHT and EGF up-regulated cyclinD1 (CD1) at both mRNA and protein levels in A549 cells, while in LNCaP cells each mitogen increased only CD1 protein expression. In both cell contexts, CD1 up-regulation was prevented by selective inhibitors as well as by knock-down of either AR or EGFR and also inhibiting p38MAPK and the mammalian target of rapamycin (mTOR) pathways. Interestingly, p38MAPK and mTOR repression prevented the activation of the mTOR target ribosomal p70S6 kinase induced by DHT and EGF, indicating that p38MAPK acts as an upstream mTOR regulator. In addition, the proliferative effects promoted by both DHT and EGF in LNCaP and A549 cancer cells were no longer observed blocking either p38MAPK or mTOR activity. Hence, our data suggest that p38MAPK-dependent activation of the mTOR/CD1 pathway may represent a mechanism through which AR and EGFR cross-talk contributes to prostate and lung cancer progression.
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PMID:A cross-talk between the androgen receptor and the epidermal growth factor receptor leads to p38MAPK-dependent activation of mTOR and cyclinD1 expression in prostate and lung cancer cells. 1869 55

Mammary Paget's disease (MPD) is a rare manifestation of breast carcinoma involving the nipple. Our objective was to identify molecular markers and molecular subtypes that may predict patients at high risk of developing MPD. Immunohistochemical (IHC) analyses were performed with antibodies to estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), HER2, epidermal growth factor receptor (EGFR), and several cytokeratins (CK5/6, CK14, CK17, CK8, CK18) on representative sections of 121 cases of ductal carcinoma of the breast, including 28 cases with MPD, 81 cases with neither MPD nor nipple involvement, and 12 cases of non-MPD with nipple involvement. The rates of receptor expression and subtype distributions of 3 IHC-based molecular classifications were compared among these groups. The results showed that: (1) MPD is more likely to be associated with ER- and PR-negative ductal carcinoma in situ (DCIS), but not invasive ductal carcinoma (IDC); (2) MPD is more likely to be associated with HER2-over expression subtype DCIS, but not IDC; and (3) carcinomas with non-MPD nipple involvement differ from those with MPD, since they are more likely to be ER- and PR-positive, HER2-negative, and luminal A subtype. In summary, different panels of markers should be used to predict MPD associated with different underlying lesions; for DCIS, the ER-negative, PR-negative, and HER2-subtype and not basal-like subtype is most predictive of MPD; for IDC, the luminal B-subtype is most predictive of MPD.
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PMID:Different panels of markers should be used to predict mammary Paget's disease associated with in situ or invasive ductal carcinoma of the breast. 1920 36

A total of 21 metaplastic breast carcinomas (MCs) with chondroid differentiation were evaluated to better establish the clinicopathological features of this variant. The tumors exhibited mainly invasive carcinoma admixed with areas of cartilaginous matrix production. An associated ductal intraepithelial neoplasia component grade 2 or 3 was observed in 43% of cases. Immunohistochemical analysis revealed a triple negative (ER-, PR-, and Her2/neu-) immunoprofile and no expression of the androgen receptor. EGFR-positivity was found in 88% of evaluated cases, consistent with the proposed basaloid phenotype for all MC. Compared with previous studies that reviewed MC with osseus and cartilaginous elements, the incidence of axillary lymph node metastasis was significantly higher in our study and 60% of positive nodes exhibited chondroid differentiation. Available follow-up data (n = 10) revealed aggressive behavior of this MC variant with frequent metastasis, including visceral involvement and local chest wall recurrence despite chemotherapy and radiation. Three patients subsequently died of metastatic disease.
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PMID:Breast carcinoma with chondroid differentiation: a clinicopathologic study of 21 triple negative (ER-, PR-, Her2/neu-) cases. 1928 92

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR and ERBB2 expression in PCa cells. In steroid-depleted medium (SDM), EGFR protein was less abundant in androgen-sensitive LNCaP than in androgen ablation-resistant 22Rv1 cells, whereas transcript levels were similar. Dihydrotestosterone (DHT) treatment increased both EGFR mRNA and protein levels and stimulated RNA polymerase II recruitment to the EGFR gene promoter, whereas it decreased ERBB2 transcript and protein levels in LNCaP cells. DHT altered neither EGFR or ERBB2 levels nor the abundance of prostate-specific antigen (PSA), TMEPA1, or TMPRSS2 mRNAs in 22Rv1 cells, which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain (ARDeltaCTD). The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms. Silencing of both isoforms strongly reduced PSA, TMEPA1, and TMPRSS2 transcript levels. Inhibition of both AR isoforms did not affect EGFR and ERBB2 transcript levels but decreased EGFR and increased ERBB2 protein levels. Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARDeltaCTD. A further decrease was obtained with PKI166, an EGFR/ERBB2 kinase inhibitor. Overall, we showed that ARDeltaCTD is responsible for constitutive EGFR expression and ERBB2 repression in 22Rv1 cells and that ARDeltaCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth.
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PMID:Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines. 1931 61


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