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)

Breast cancer is the most common cancer among women and about 80% of breast cancers express hormone receptors. Tamoxifen has been the most important form of adjuvant endocrine therapy over the last 25 years. The third generation aromatase inhibitors (AIs) are a new class of drugs challenging the central role of tamoxifen as adjuvant endocrine treatment in postmenopausal women with hormone receptor-positive breast cancer. Their effectiveness has been demonstrated in first line therapy as well in neoadjuvant setting with a statistically significant superiority over tamoxifen. Here we considered the role of adjuvant AIs in early stage breast cancer with an analysis reviewing the main adjuvant trials. We considered efficacy, side effects, optimal timing, duration of the therapy and whether specific subgroups may achieve particular benefit. In conclusion the upfront use of adjuvant anastrozole or letrozole is superior to tamoxifen with a good relative toxicity profile. Tamoxifen will continue to have a role where recurrence risk is low or if AI is poorly tolerated. Issues including the timing of administration (up-front or sequential), the duration of the therapy and the role of biomarkers such as PgR and HER2 in optimal selection remain unresolved.
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PMID:Adjuvant endocrine therapy for early breast cancer. 1715 Mar 3

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.
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PMID:BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. 1719 28

The liver is a major metabolic and endocrine organ in growing neonates, but the extent to which its hormone receptor (R) sensitivity is potentially determined by maternal parity and the mother's nutritional environment is unknown. This was therefore investigated by sampling livers from postnatal sheep born to nulliparous or multiparous mothers. Offspring were sampled 1 or 30 days after birth from mothers consuming either 100 or 50% [i.e., nutrient-restricted (NR) group] of total metabolizable energy requirements from 110 days gestation to term ( approximately 147 days). Regardless of maternal diet, offspring of nulliparous mothers were lighter at birth and had smaller livers. By 1 mo of age, they exhibited catch-up growth, an adaptation not seen when mothers were NR, but they retained their lighter livers. At both sampling ages, livers from offspring born to nulliparous mothers exhibited increased mRNA abundance for growth hormone (GH) receptor, IGF-IR, plus hepatocyte growth factor (HGF); and at day 1 only IGF-I, but not IGF-IIR mRNA was decreased. In addition, mRNA for IGF-II, the HGFR, c-Met, and Bax were persistently reduced in these offspring. Effects of parity were largely unaffected by maternal nutrient restriction. Maternal parity therefore has a substantial effect on liver size during postnatal development and its receptor population that is not dependent on maternal diet. First-born offspring appear to exhibit a resetting of the endocrine control of hepatic growth within the HGF and GH-IGF axis, which could have later consequences after their growth has caught up.
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PMID:Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. 1720 89

Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal-like phenotype. Basal-like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C-terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal-like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal-like breast carcinomas and also with metaplastic breast cancers with a basal-like phenotype; the comparison showed that we have generated a mouse model of basal-like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer.
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PMID:A mouse model of basal-like breast carcinoma with metaplastic elements. 1721 42

It is not clear whether invasive breast carcinomas with medullary features (IBCMFs, atypical medullary carcinomas) constitute a specific phenotype of breast cancer that is of biologic significance. Because medullary features are common in BRCA1-associated carcinomas and these tumors frequently show a basal-like phenotype, we examined whether IBCMFs expressed basal/myoepithelial markers and had a basal-like phenotype. We studied the immunohistochemical expression of 15 markers in tissue microarrays containing samples from 35 IBCMFs and 39 grade 3 invasive ductal carcinomas (IDCG3s) of no special type. In addition, we analyzed EGFR, C-MYC, and CCNE gene amplification by fluorescence in situ hybridization, because the expression of these genes is known to be associated with the basal-like phenotype. We defined the basal-like phenotype according to the criteria of Nielsen et al as being those tumors that were ER/HER2-negative and cytokeratin (CK) 5/6- and/or epidermal growth factor receptor-positive. IBCMFs were more frequently hormone receptor- and HER2-negative, but had greater expression of proliferation markers and p53. In addition, IBCMFs more frequently expressed basal/myoepithelial markers, such as CK5/6 and P-cadherin. A basal-like phenotype was found in 62.9% of IBCMFs but in only 18.9% of IDCG3s. No differences in gene amplification were found between IBCMFs and IDCG3s, although C-MYC amplification was more common in tumors without a basal-like phenotype. The identification of IBCMF as an independent group of tumors could be of clinical significance, given the high incidence of cases with a basal-like phenotype, which is a group of tumors with different prognosis and chemotherapy response from those of IDCG3s of no special type.
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PMID:Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study. 1741 96

Evidence suggests that breast cancer hormone receptor status varies by etiologic factors, but studies have been inconsistent. In a population-based case-control study in Poland that included 2,386 cases and 2,502 controls, we assessed ER-alpha and PR status of tumors based on clinical records according to etiologic exposure data collected via interview. For 842 cancers, we evaluated ER-alpha, ER-beta, PR and HER2 levels by semiquantitative microscopic scoring of immunostained tissue microarrays and a quantitative immunofluorescence method, automated quantitative analysis (AQUAtrade mark). We related marker levels in tumors to etiologic factors, using standard regression models and novel statistical methods, permitting adjustment for both correlated tumor features and exposures. Results obtained with different assays were generally consistent. Receptor levels varied most significantly with body mass index (BMI), a factor that was inversely related to risk among premenopausal women and directly related to risk among postmenopausal women with larger tumors. After adjustment for correlated markers, exposures and pathologic characteristics, PR and HER2 AQUA levels were inversely related to BMI among premenopausal women (p-trend = 0.01, both comparisons), whereas among postmenopausal women, PR levels were associated directly with BMI (p-trend = 0.002). Among postmenopausal women, analyses demonstrated that BMI was related to an interaction of PR and HER2: odds ratio (OR) = 0.86 (95% CI = 0.69-1.07) for low PR and HER2 expression vs. OR = 1.78 (95% CI = 1.25-2.55) for high expression (p-heterogeneity = 0.001). PR and HER2 levels in breast cancer vary by BMI, suggesting a heterogeneous etiology for tumors related to these markers.
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PMID:Variation in breast cancer hormone receptor and HER2 levels by etiologic factors: a population-based analysis. 1748 43

Despite the rapid expansion of novel diagnostics designed to personalize breast cancer care, there remain several significant unmet needs for improving the accuracy and reliability of tests that are already in common daily clinical practice. For example, although immunohistochemistry has been the predominant method for measuring estrogen receptor and progesterone receptor status for over 15 years, this assay remains unstandardized and there is a widespread concern that inaccuracy in immunohistochemistry technique and interpretation is leading to an unacceptably high error rate in determining the true hormone receptor status. Similarly, there is considerable concern that both false-negative and false-positive result rates for testing for HER2 status are unacceptably high in current clinical practice. This commentary considers a variety of factors, including preanalytic conditions and slide-scoring procedures, and other variables that may be contributing to current testing error rates and why there is a great need for the standardization of these biomarker assay procedures to further enable the highest possible quality of care for newly diagnosed breast cancer patients.
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PMID:Standardizing slide-based assays in breast cancer: hormone receptors, HER2, and sentinel lymph nodes. 1750 80

Taxanes (TX) were administered to 246 of 292 patients with recurrent/metastatic breast cancer (MBC) who were treated in Hiei Hospital between January 2001 and May 2006. Recently, TX has been increasingly prescribed for preoperative treatment and postoperative adjuvant therapy. To improve the prognosis of MBC, regimens effective for TX-resistant cancer patients should be developed. In this study, with respect to hormone receptor (HR) and Her 2/neu (HER 2), we retrospectively investigated whether our series responded to the regimens used after TX resistance was acquired. As post TX-resistance therapy (trastuzumab was combined in HER2-positive patients), 387 treatment regimens were administered to 166 patients. The following regimens achieved a response rate (patients achieving PR or CR/patients who could be evaluated) of 10% or more: combination therapy with TX and capecitabine (11/61, 18%), CPT-11 (10/57, 17.5%), vinorelbine (5/46, 10.9%), MFL-P (continuous treatment with MTX, 5-FU, LV, and CDDP) (12/47, 25.5%), and DMpC (5'-DFUR, MPA, CPA p.o.) (5/16, 31.2%). The latter 2 regimens achieved a high response rate,and some HR (-) and HER 2 (-) patients also responded to these regimens. In HR (+) or HER 2 (+) patients who responded to TX, survival was longer than that of non-responders. However, there was no difference in the treatment responsiveness of post-TX regimens between TX-responders and non-responders, suggesting the survival-prolonging effect of TX.
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PMID:[Evaluation of therapeutic regimens for taxane-resistant recurrent/metastatic breast cancer]. 1763 40

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR- cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P<0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P=0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P=0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2- cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P=0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.
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PMID:Letrozole in the neoadjuvant setting: the P024 trial. 1791 34

The insulin-like growth factor 1 (IGF1) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3) play a pivotal role during the growth and development of tissues. The purpose of this study was to evaluate the influence of anthracycline- and taxane-containing adjuvant chemotherapy in breast cancer patients on the circulating plasma levels of IGF1 and its main binding protein, IGFBP3. This investigation was part of a prospective randomized phase III study in which breast cancer patients were treated with either conventional or dose-intensified adjuvant chemotherapy. The factors were quantified in the plasma of 151 patients with a commercially available sandwich enzyme immunoassay. Before therapy, both parameters were within the normal range in most patients (n=145 and n=144). After therapy, both factors had increased significantly by 29% (IGF1) and 19% (IGFBP3), with the highest increase being observed in the dose-intensified group. Correlations with patient and tumor characteristics revealed a relatively higher increase in both parameters in premenopausal patients, patients with lower-grade tumors, more positive lymph nodes, larger tumor volume, and positive hormone receptor status. No correlation was found with the HER2 expression of the tumors.
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PMID:Significant changes in circulating plasma levels of IGF1 and IGFBP3 after conventional or dose-intensified adjuvant treatment of breast cancer patients with one to three positive lymph nodes. 1792 61


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