TRAF2 is an NF-κB-activating oncogene in epithelial cancers.

Aberrant nuclear factor (NF)-κB activation is frequently observed in human cancers. Genome characterization efforts have identified genetic alterations in multiple components of the NF-κB pathway, some of which have been shown to be essential for cancer initiation and tumor maintenance. Here, using patient tumors and cancer cell lines, we identify the NF-κB regulator, TRAF2 (tumor necrosis factor (TNF) receptor-associated factor 2), as an oncogene that is recurrently amplified and rearranged in 15% of human epithelial cancers. Suppression of TRAF2 in cancer cells harboring TRAF2 copy number gain inhibits proliferation, NF-κB activation, anchorage-independent growth and tumorigenesis. Cancer cells that are dependent on TRAF2 also require NF-κB for survival. The phosphorylation of TRAF2 at serine 11 is essential for the survival of cancer cells harboring TRAF2 amplification. Together, these observations identify TRAF2 as a frequently amplified oncogene.

h-Caldesmon expression effectively distinguishes endometrial stromal tumors from uterine smooth muscle tumors.

Distinction of endometrial stromal neoplasms from cellular smooth muscle tumors of the uterus is sometimes difficult. Immunohistochemistry is often not helpful because muscle actins and desmin are expressed in both neoplasms. This study's goal was to determine whether h-caldesmon, a smooth muscle-specific isoform of a calcium, calmodulin, and actin binding protein, could effectively distinguish endometrial stromal tumors from uterine smooth muscle tumors. The authors analyzed immunohistochemical expression in 24 endometrial stromal neoplasms (21 sarcomas and three nodules), 29 leiomyosarcomas, 32 leiomyomas (10 "usual," 14 cellular leiomyoma, and eight "highly cellular" types), 40 myometria, and 25 endometria. h-Caldesmon was diffusely positive in all myometria, leiomyomata, and leiomyosarcomas. Of note, 16 leiomyosarcomas (55%) were positive for h-caldesmon in more than 50% of tumor cells. In five "highly cellular" leiomyomas, h-caldesmon expression was markedly decreased or absent in areas morphologically resembling endometrial stromal tumors, raising the possibility that these tumors may be mixed smooth muscle-endometrial stromal neoplasms. In contrast, h-caldesmon expression was absent in all endometria and endometrial stromal neoplasms apart from accompanying small vessels. Desmin was diffusely positive in all myometria and leiomyomata. The fraction of cells expressing desmin was greater than that of h-caldesmon in only 10% of leiomyosarcomas. Focal desmin expression was also present in eight of 25 (32%) endometria and 12 of 24 (50%) endometrial stromal neoplasms. h-Caldesmon appears to be a more sensitive and specific marker of smooth muscle differentiation in the uterus than desmin and may be a useful tool for distinguishing and classifying uterine mesenchymal tumors.

Identification of a basal/reserve cell immunophenotype in benign and neoplastic endometrium: a study with the p53 homologue p63.

BACKGROUND: Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations. METHODS: One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC). RESULTS: p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells. CONCLUSIONS: Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

Differential expression of MUC2 and MUC5AC in benign and malignant glandular lesions of the cervix uteri.

The expression of mucin genes in the normal glandular epithelium of the endocervix has been well characterized. However, mucin gene expression in neoplastic or particular non-neoplastic glandular cervical lesions has not been addressed. This immunohistochemical study was carried out to analyze the expression of MUC2 and MUC5AC in neoplastic and non-neoplastic glandular lesions of the cervix. Monoclonal antibodies were used on paraffin-embedded sections from 41 adenocarcinomas, 2 adenosquamous carcinomas, 13 adenocarcinomas in situ (ACIS), 3 glandular dysplasias, 8 endometrioses, 5 tubal metaplasias, 17 squamous metaplasias, 3 microglandular hyperplasias and normal tissue of the endocervix, endometrium and fallopian tube. The patterns of expression of MUC2 and MUC5AC were different and in principle contrary. Focal MUC2 expression was observed almost exclusively in neoplastic lesions (36%) and not in normal epithelia and non-neoplastic lesions, the one notable exception being immature metaplasia. In contrast, strong expression of MUC5AC was observed in both normal endocervical epithelium (100%) and neoplastic lesions (73%). The expression of MUC5AC, however, was diminished in most neoplastic glandular lesions. Co-expression of MUC2 and MUC5AC was consistently documented in the lesions with intestinal differentiation. In contrast, cases of tubal metaplasia and endometriosis were negative for MUC2 and MUC5AC. These results indicate that discrimination of mucin gene expression may be helpful in discriminating lesions of the cervix.

Adult polycystic liver disease with cutaneous involvement: a brief report.

This case report documents the largest example of adult polycystic liver disease reported to date. In addition, the patient was found to have numerous subcutaneous cysts, an association with polycystic disease, which, as far as we could determine from the literature, has not previously been reported.

Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis.

Mucinous carcinomas of the breast, so-called colloid carcinomas, exhibit better prognoses than their nonmucinous breast counterparts. This biological difference exhibited by mucinous breast carcinomas prompted us to examine the relationship of mucin expression to colloid carcinoma histogenesis. We studied 50 colloid carcinomas, 50 noncolloid cancers, and 50 normal breasts by hematoxylin-eosin (H&E) and Alcian blue staining, mucin immunohistochemistry, in situ hybridization with a battery of MUC riboprobes, and ancillary digital image analysis. We observed luminal mucin in normal ducts in 80% of colloid carcinomas compared with 10% of noncolloid carcinomas and 6% of normal breasts (P < .01). In the cases of colloid carcinoma that showed mucin-filled ducts, luminal mucin was observed in 40% of the normal ducts and acini, 40% to 75% of the ducts involved by hyperplasia, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), respectively, and in 50% of the co-incidental areas of cysts (mucoceles), adenosis, fibroadenoma, and intraductal papilloma (P < .01). Immunohistochemistry showed that colloid carcinomas showed strong MUC2 cytoplasmic immunoreactivity and decreased MUC1 immunoreactivity compared with noncolloid carcinomas. In situ hybridization studies indicated fivefold increased MUC2 signals and twofold increased MUC5 signals within adjacent and remote normal epithelium in only the colloid carcinoma cases (P < .01; P < .05). In these cases of colloid carcinoma, these increased MUC2 and MUC5 signals were also observed in areas of hyperplasia, ADH, DCIS, and invasive carcinoma. In contrast, the noncolloid carcinomas showed fivefold increased MUC1 signals but no increases in MUC2 or MUC5. In mixed colloid/noncolloid carcinomas, the colloid areas had identical mucin expression patterns as the pure colloid carcinomas, but there was a loss of MUC2 and MUC5 expression and a gain of MUC1 expression in the noncolloid areas that was therefore identical to the pattern observed in pure noncolloid carcinoma. In this study, we conclude that the altered expression of mucin so characteristic of colloid carcinoma is also a field change present in adjacent and remote normal breast epithelium.

The human myoepithelial cell exerts antiproliferative effects on breast carcinoma cells characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis.

Ductal carcinoma in situ of the breast (DCIS) is surrounded by a layer of myoepithelial cells. Our previous studies have suggested that these myoepithelial cells exert paracrine tumor-suppressive effects on invasion of breast carcinoma cells. Conditioned medium (CM), concentrated 10-100x of HMS-1, HMS-3, and HMS-4, human myoepithelial cell lines, block Matrigel invasion of a series of carcinoma cell lines. Immunoprecipitation of maspin, a recently described serpin, from these CM abolishes this anti-invasive effect. Both CM and maspin-immunoprecipitated CM, however, exert equal antiproliferative effects on a series of ER+ and ER- cell lines including MCF-7, T47D, MDA-MB-231, and MDA-MB-468. These antiproliferative effects are characterized by induction of a G2/M arrest, a twofold increase in p21(WAF1/CIP1) transcription and expression, and a threefold increase in apoptosis in the breast carcinoma lines examined. The antiproliferative effects mediated by myoepithelial cell CM do not manifest themselves in an autocrine manner, are not mediated by TGF-beta1, nor involve ER- or p53-dependent pathways. Neither the antiproliferative nor the anti-invasive effects of myoepithelial cell CM is observed with nonmyoepithelial cell CM. The in vitro observations of our present study may have relevance in explaining the increased degree of apoptosis exhibited by DCIS cells in vivo. Our findings illustrate another way myoepithelial cells function as natural paracrine tumor suppressors.

Glucose-6-phosphate dehydrogenase revisited.

Hemolytic diseases associated with drugs have been recognized since antiquity. Many of these anemias have been associated with oxidizing agents and deficiencies in the intraerythrocytic enzyme glucose-6-phosphate dehydrogenase. This paper outlines the discovery, prevalence, and variants of this enzyme. Methods of diagnosis of associated anemias are offered.