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:P10721 (c-kit)
6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenoid cystic carcinoma of the breast represents a unique clinicopathologic entity with a variable histological appearance and a relatively indolent clinical course in most of the cases. Adenoid cystic carcinoma may be difficult to differentiate from infiltrating duct carcinomas, and in particular from tubular and cribriform carcinomas, especially in core or vacuum-assisted biopsies. We evaluated the prevalence of c-kit, p63, and e-cadherin immunoreactivity in a series of 20 adenoid cystic carcinomas, comparing the results with those obtained in a series of infiltrating tubular carcinomas and infiltrating cribriform carcinomas. The hormone receptor status, proliferation labeling index, and HER/2 immunoreactivity had been previously investigated in all the cases. Three (15%) adenoid cystic carcinomas and all infiltrating tubular and cribriform carcinomas showed estrogen receptor and/or progesterone receptor immunoreactivity (P < 0.00001 for estrogen and P = 0.00002 for progesterone receptors). Adenoid cystic carcinomas consistently lacked any immunoreactivity for HER/2, whereas three (15%) infiltrating and cribriform carcinomas showed weak and incomplete membrane staining (P = 0.23077). Membranous immunoreactivity for c-kit was found in all except one (predominantly basaloid) adenoid cystic carcinomas (95%), and in none of the infiltrating tubular and cribriform carcinomas (P < 0.00001). Nuclear immunoreactivity for p63 was found in all except three (predominantly basaloid) adenoid cystic carcinomas (85%) and in none of the infiltrating tubular and cribriform carcinomas (P < 0.00001). All infiltrating tubular and cribriform carcinomas and 18/20 (90%) adenoid cystic carcinomas showed immunoreactivity for e-cadherin (P = 0.48718). In summary, adenoid cystic carcinomas showed the following phenotype: estrogen receptor-/progesterone receptor-/c-kit+/p63+ (13 cases, 65%), estrogen receptor-/progesterone receptor/c-kit+/p63- (three cases, 15%), estrogen receptor-/progesterone receptor-/c-kit-/p63+ (one case, 5%), estrogen receptor+/progesterone receptor+/c-kit+/p63+ (two cases, 10%), and estrogen receptor+/progesterone receptor-/c-kit+/p63+ (one case). By contrast, all the infiltrating tubular and cribriform carcinomas showed the estrogen receptor+/progesterone receptor+/c-kit-/p63- phenotype. Our data provide evidence that immunoreactivity for c-kit and/or p63 may be useful in differentiating adenoid cystic carcinomas from other types of breast cancer.
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PMID:Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. 1584 89

Gene-expression profiling can help distinguish between patients at high risk and those at low risk for developing distant metastases, and so identify patients for adjuvant therapy. For several years, the Netherlands Cancer Institute has been working on gene-expression profiling of breast cancer using a microarray platform containing 25,000 genes. Using supervised classification, a prognostic classifier consisting of 70 genes could be identified. In addition to providing prognostic information, gene profiling should also enable us to detect patients who are likely to respond to particular adjuvant interventions. Well-known predictors for response to systemic therapy include estrogen receptor status HER-2 status, c-kit mutation, and epidermal growth factor receptor mutation. Because of the long periods required for predicting responsiveness in the adjuvant setting, neoadjuvant trials promise far quicker results. Several neoadjuvant studies are under way or planned to investigate gene-expression profiling as a means of predicting the therapeutic response to docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), cyclophosphamide, and doxorubicin (Adriamycin; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) in breast cancer patients. It is expected that in the coming years an increasing number of novel prognostic and predictive tests will help in guiding the adjuvant systemic treatment of breast cancer and other malignancies.
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PMID:Gene-expression profiling and the future of adjuvant therapy. 1627 57

Basal-like carcinomas have recently been identified in gene expression profiling studies as a subtype of invasive breast cancer. These lesions are estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative (triple negative), and typically express basal cytokeratins, epidermal growth factor receptor (EGFR), and/or c-kit. As poorly differentiated invasive ductal carcinomas, they presumably have a ductal carcinoma in situ (DCIS) precursor with similar cytologic and immunophenotypic features. However, the frequency and even the existence of a DCIS lesion with an immunophenotype analogous to that of invasive basal-like carcinomas have not been previously evaluated. We studied 66 cases of high nuclear grade DCIS using antibodies to ER, PR, HER2, three basal cytokeratins, EGFR, and c-kit to determine the frequency of the triple negative phenotype, and to determine the relationship between the triple negative phenotype and expression of basal cytokeratins and other biomarkers characteristically expressed by invasive basal-like carcinomas. Four cases (6%) exhibited the triple negative phenotype; the remaining cases showed other combinations of ER, PR, and HER2 expression (nontriple negative). Basal cytokeratins, EGFR, or both were expressed by all four triple negative lesions, but by only 21 of 51 (42%) nontriple negative cases (P = 0.04). We conclude that a small proportion of high-grade ductal carcinomas in situ exhibit an ER-negative/PR-negative/HER2-negative (triple negative) phenotype, and these lesions more commonly show expression of basal cytokeratins and/or EGFR than nontriple negative high-grade DCIS. Given that invasive breast cancers typically share immunophenotypic features with the ductal carcinoma in situ from which they arise, our findings raise the possibility that the triple-negative, basal cytokeratin and/or EGFR-positive DCIS lesions we identified represent a precursor lesion to invasive basal-like carcinomas.
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PMID:Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer. 1652 77

DNA microarray profiling studies have led to the classification of invasive breast carcinoma into luminal/estrogen receptor-positive, normal breast-like, Her2/neu-overexpressing, and basal-like types. Among these groups, the basal-like subtype is associated with the poorest clinical outcome in Western countries. To date, the clinicopathologic characteristics of the basal-like carcinomas, compared with other subtypes, have not been described in the Korean population. In this study, we used tissue microarray to examine the expression of basal cytokeratins (CK) (CK5 and CK14) and luminal CK (CK8/18), epidermal growth factor receptor, c-kit, hormone receptors (HRs), p53, and Her2/neu in 776 consecutive patients diagnosed with invasive breast carcinoma from January 1993 to December 1998 and categorized these cases into 5 subgroups (basal-like, HR-expressing, Her2/neu-overexpressing, HR and Her2/neu-expressing, and null subtypes negative for all markers), based on the immunohistochemical data. We identified cases of 114 (14.7%) basal-like, 345 (44.5%) HR-expressing, 133 (17.1%) Her2/neu-overexpressing, 61 (7.8%) HR and Her2/neu-expressing, and 123 (15.9%) null subtypes. Histologically, most basal-like breast cancers were invasive ductal carcinoma, not otherwise specified (98 cases, 86.0%), with high nuclear and/or histologic grades, and most metaplastic carcinomas (6 [75.0%] of 8 cases) were the basal-like subtype. Both basal-like and Her2/neu-overexpressing subtypes were associated with larger tumor sizes (mean, 3.6 and 3.3 cm, respectively) than the HR-expressing group (mean, 2.8 cm) (P = .001 and P = .036, respectively). Nodal stage of Her2/neu-overexpressing subtype was higher than that of basal-like subtype; however, overall stage was not different between the 2 groups (P = .010 and .123, respectively). Distant metastasis was most frequently observed in the Her2/neu-overexpressing subtype (33.8%), which was prognostically the worst subgroup of breast cancers. In contrast to previous findings from Western countries, our analyses reveal that the Her2/neu status is the most important prognostic factor of breast cancers.
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PMID:Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. 1693 28

Signal transduction pathways play a crucial role in breast cancer development, progression, and response to different therapies. A major problem in breast cancer therapy is the heterogeneity among different tumor types and cell lines commonly used in preclinical studies. To characterize the signaling pathways of some of the commonly used breast cancer cell lines and dissect the relationship among a number of pathways and some key genetic and molecular events in breast cancer development, such as p53 mutation, ErbB2 expression, and estrogen receptor (ER)/progesterone receptor (PR) status, we performed pathway profiling of 14 breast cancer cell lines by measuring the expression and phosphorylation status of 40 different cell signaling proteins with 53 specific antibodies using a protein lysate array. Cluster analysis of the expression data showed that there was close clustering of phosphatidylinositol 3-kinase, Akt, mammalian target of rapamycin (mTOR), Src, and platelet-derived growth factor receptor beta (PDGFRbeta) in all of the cell lines. The most differentially expressed proteins between ER- and PR-positive and ER- and PR-negative breast cells were mTOR, Akt (pThr308), PDGFRbeta, PDGFRbeta (pTyr751), panSrc, Akt (pSer473), insulin-like growth factor-binding protein 5 (IGFBP5), Src (pTyr418), mTOR (pSer2448), and IGFBP2. Many apoptotic proteins, such as apoptosis-inducing factor, IGFBP3, bad, bax, and cleaved caspase 9, were overexpressed in mutant p53-carrying breast cancer cells. Hexokinase isoenzyme 1, ND2, and c-kit were the most differentially expressed proteins in high and low ErbB2-expressing breast cancer cells. This study demonstrated that ER/PR status, ErbB2 expression, and p53 status are major molecules that impact downstream signaling pathways.
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PMID:Dissection of signaling pathways in fourteen breast cancer cell lines using reverse-phase protein lysate microarray. 1712 30

Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine- and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropoiesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling.
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PMID:Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. 1823 84

Microglandular adenosis (MGA) of the breast is widely known as a benign lesion that can mimic invasive carcinoma. In situ and invasive carcinomas have been described as arising in MGA, but which cases of MGA will progress to carcinoma is unclear. Criteria for distinguishing uncomplicated MGA, MGA with atypia (AMGA), and carcinoma arising in MGA (MGACA) are not standardized. The primary objective of this study was to illustrate the clinical, histopathologic, and immunophenotypical characteristics of MGA, AMGA, and MGACA in an effort to provide criteria for distinguishing the 3 types. We retrospectively identified 108 cases seen at M.D. Anderson Cancer Center between 1983 and 2007 that had a diagnosis of MGA. Of the 108 cases, 65 cases had available material for review. Inclusion criteria were glands of MGA expressing S-100 protein and lacking myoepithelial layer (smooth muscle actin negative). Eleven out of 65 cases qualified to have an MGA component; myoepithelial layer was detected in the remaining 54 cases and were classified as adenosis. Out of the 11 MGA patients, there were 3 patients with uncomplicated MGA, 2 had AMGA, and 6 had MGACA. Staining indices for the cell cycle markers p53 and Ki-67 were used to compare the 3 tumor categories. Additional staining for other tumor markers [estrogen and progesterone receptors, HER2, epidermal growth factor receptor (EGFR), c-kit, CK5/6, and CK18] were performed. Patient demographics, tumor radiologic features, and clinical follow-up data were collected for all cases. Multiple invasive histologic components were identified in each of the MGACA cases. All invasive MGACAs had a duct-forming component. In addition, basal-like component was present in 2 cases, aciniclike in 2, matrix producing in 4, sarcomatoid in 1, and adenoid cystic in 1. All tumors had strong and diffuse CK8/18 and EGFR expression but no estrogen receptor, progesterone receptor, HER2 (ie, triple negative), or CK5/6 expression. C-kit was focally expressed in 2 of the MGACAs. Ki-67 and p53 labeling indices was < 3% in all MGAs, 5% to 10% in the AMGAs, and > 30% in MGACAs. In a follow-up ranging from 14 days to 8 years, none of the MGA cases recurred. One of the AMGA cases recurred as invasive carcinoma in a background of AMGA after 8 years following incomplete excision of the lesion. Three out of 6 MGACA cases (50%) required multiple consecutive resections ending up with mastectomy due to involved margins by invasive or in situ carcinoma. Two out of 6 MGACA cases (34%) developed metastasis and died of disease. Our data showed that Ki-67 and p53 expression, in conjunction with the morphologic features, could be a reliable marker to distinguish MGA from AMGA and MGACA. Although 11 tumors were only included in our study, 64% of the tumors were carcinomas arising in MGA. This high incidence of MGACA may not represent the actual frequency of MGAs progressing into carcinoma and is likely due to referral bias in our institution. Nonetheless, the high association of carcinoma with MGA necessitates complete excision of MGA to rule out invasion. Although all the MGACA cases were triple negative and express EGFR (basal-like features), all the cases in our study showed a luminal type of differentiation by CK8/18 expression, indicating that MGACA may not fit well into the current proposed molecular classification of breast cancer.
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PMID:Clinical, histopathologic, and immunohistochemical features of microglandular adenosis and transition into in situ and invasive carcinoma. 1830 Jul 93

Mullerian adenosarcomas (MAs) are rare mixed mesenchymal and epithelial neoplasms that occur most commonly in the uterus. Although the epithelial component is typically benign, the mesenchymal component of most adenosarcomas morphologically resembles that observed in endometrial stromal tumors and is responsible for their clinical behavior. Thus, the differential diagnosis usually includes not only low-grade endometrial stromal tumors, but also adenofibroma, carcinosarcoma, and embryonal rhabdomyosarcoma especially in small samples. The objective of this study was to ascertain the immunophenotypic profile of the epithelial and mesenchymal components of MAs and delineate possible differences between conventional mesenchymal areas and areas of sarcomatous overgrowth. Representative sections from 35 MAs, 28 of them without sarcomatous overgrowth (MA-NSO) and 7 with sarcomatous overgrowth (MA-SO), were included in the study. Thirty tumors arose in the uterus, 4 were pelvic, and 1 originated in the colon. Adequate blocks were selected and immunostained for estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), CD10, WT1, smooth muscle actin, desmin, AE1/3 cytokeratin, CD34, calretinin, inhibin, c-kit, and Ki-67. The mesenchymal component expressed ER in 21/27 MA-NSOs but in only 1/7 MA-SOs (65% overall). PR was expressed in 21/26 MA-NSOs and 4/7 MA-SOs (76% overall), whereas AR was positive in 10/27 MA-NSOs and 5/7 MA-SOs (35% overall). CD10 was expressed in 23/28 MA-NSOs but in only 2/7 MA-SOs (71% overall), and WT1 positivity was seen in 22/27 MA-NSOs and 6/7 MA-SOs (79% overall). Sixty-seven percent of MAs expressed smooth muscle actin, 32% desmin, including both examples of MA-SOs with rhabdomyoblastic differentiation, and 25% expressed AE1/3 cytokeratin. CD34 expression was found in 35% of the tumors, but it was almost always patchy in distribution and weak in intensity, as was calretinin expression, seen only in 12% of the cases. Expression of c-kit and inhibin in greater than 5% of the tumor cells was not encountered. The median and mean Ki-67 labeling indices were 10% and 12%, respectively (range, <5% to 40%). The median and mean Ki-67 indices were both 5% in MA-NSOs compared with 30% and 28%, respectively, in MA-SOs. The epithelial compartment demonstrated expression for ER (24/32), PR (23/31), and AE1/3 cytokeratin (33/33); rare cases expressed CD10 (4 cases) and AR (1 case). In summary, the immunophenotype of most MAs resembled that of endometrial stromal tumors (positive for ER, PR, WT1, and CD10, with variable expression of muscle markers, AR and cytokeratin). The proliferative rate in the stromal component was strongly related to the presence of sarcomatous overgrowth. ER, PR, and CD10 expression was lost in MA-SOs relative to conventional low-grade stromal areas of mullerian/mesodermal adenosarcomas, reflecting the "dedifferentiation" of this component.
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PMID:Mullerian adenosarcomas: an immunophenotypic analysis of 35 cases. 1846 8

The present study was designed to investigate the relationship between pre-mating nutrition and the relative amounts of a panel of developmentally relevant genes in ovine oocytes and granulosa cells. Cast age ewes were fed a ration providing 0.5x (0.5 M) or 1.5x (1.5 M) live weight maintenance requirements for 2 weeks before slaughter. The ewes were synchronized and superovulated with FSH and pregnant mares serum gonadotropin. At slaughter, oocytes and granulosa cells were aspirated from follicles >2 mm in diameter and the relative abundance of 8 and 17 transcripts in oocytes and granulosa cells respectively were analyzed by semi-quantitative RT-PCR. In the oocytes, no differences between groups were observed for five transcripts (GDF9, BMP15, c-kit, glucose transporter 1 (SLC2A1), and hexokinase 1), but a lower amount of glucose transporter 3 (SLC2A3), sodium/glucose cotransporter 1 (SLC5A1), and Na(+)/K(+) ATPase mRNAs was detected in the 0.5 M group. Increased expression of PTGS2, HAS2, and the leptin receptor long form was observed in granulosa cells from the 0.5 M group. No differences between groups were observed for the other transcripts (early growth response factor-1, estrogen receptor-alpha, LH and FSH receptors, gremlin 1, pentraxin 3, KIT ligand, glucose transporters 1, 3, and 8, IGF1, IGF1 receptor, leptin receptor, and tumor necrosis factor-stimulated gene 6). Expression of leptin and sodium/glucose cotransporter 1 was not detected in both groups. The present data indicate that pre-mating nutrition is associated with alteration in the mRNA content in oocytes and surrounding follicle cells in ewes, which may account for the reduced reproductive performance typical of ewes that are fed a restricted ration for a short period of time before mating.
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PMID:Effects of pre-mating nutrition on mRNA levels of developmentally relevant genes in sheep oocytes and granulosa cells. 1851 15

A primary invasive micropapillary carcinoma of the breast in a 46-year-old woman is reported. Histologically, it was composed predominantly of papillary tumor cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells were positive for cytokeratin (CK) 7, estrogen receptor (ER), and progesterone receptor (PR), but negative for p53, CK 20, CD34, c-Erb-B2, CK5, epidermal growth factor receptor (EGFR), vimentin, and c-kit. MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters. Accordingly, electron microscopy showed the lack of basement membrane and presence of microvilli at the basal surface of the tumor cells. Moreover, ultrastructural examination revealed single tumor cell death characterized by patchy condensations of chromatin throughout the nucleus. These nuclear alterations were associated with the occurrence of empty cytoplasmic vacuoles, conferring a necrosis-like phenotype to this cell death. Alternative programmed cell deaths are reviewed and their morphologic distinction is discussed.
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PMID:Micropapillary carcinoma of the breast with necrosis-like cell death: a case report. 1869 1


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