Faculty Bibliography

CONTEXT: Medullary carcinoma (MC) is a special type of breast cancer that has a better prognosis than atypical medullary carcinoma (AMC) and high-grade invasive ductal carcinoma (HGIDC) with prominent lymphocytic infiltrates. What accounts for the different clinical courses of these carcinomas, despite their similar histology, is unknown. To address this issue, we performed a comparative study of amplification and overexpression of HER-2/neu and expression of several other important biochemical markers (p53, MIB1, and estrogen receptor [ER]/progesterone receptor [PR]) in these 3 cancer groups. OBJECTIVE: To evaluate HER-2/neu, p53, MIB1, and ER/PR as markers in the differential diagnosis of MC, AMC, and HGIDC.Design.-Nine cases of MC, 13 cases of AMC, and 16 cases of HGIDC with prominent lymphocytic infiltrates were identified according to strict histologic criteria. All tests were performed on formalin-fixed, paraffin-embedded archival tissues. HER-2/neu gene amplification was examined by fluorescence in situ hybridization using PathVysion HER-2 DNA probes. Expression of HER-2/neu, p53, MIB1, and ER/PR was detected by immunohistochemistry. chi2 and Student t tests were applied for statistical analyses. RESULTS: None of 9 cases of MC examined had either amplification or overexpression of HER-2/neu (0%). In contrast, HER-2/neu amplification was observed in AMC (46%, P <.025) and HGIDC (56%, P <.005). All 3 categories of tumors had similar percentages of expression of p53 (78% of MC, 77% of AMC, and 69% of HGIDC) and MIB1 (89% of MC, 92% of AMC, and 94% of HGIDC). Immunostaining for ER/PR was rarely positive in either MC or AMC, and there were no significant differences of expression of ER/PR between these 2 lesions (P >.05). However, the expression rate of ER/PR (31%/44%) in HGIDC is higher than in both MC (P =.05) and AMC (P =.01). CONCLUSIONS: Medullary carcinoma of breast is distinct from AMC and HGIDC with prominent lymphocytic infiltrates in amplification and overexpression of HER-2/neu. This difference may account for its different clinical and biological behavior, and may potentially aid in diagnosis and management of these groups of patients

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue

The androgen receptor (AR), a ligand-activated transcription factor of the steroid receptor superfamily, plays an important role in normal prostate growth and in prostate cancer. The recent identification of various AR co-factors prompted us to evaluate their possible roles in prostate tumorigenesis. To this end, we analyzed the expression of AR and eight of its co-factors by quantitative in situ RNA hybridization in 43 primary prostate cancers with different degrees of differentiation. Our results revealed nearly constant expression of AR and heterogeneous expression of AR co-factors, with increased expression of PIAS1 and Ran/ARA24, decreased expression of ELE1/ARA70, and no change in TMF1/ARA160, ARA54, SRC1, or TRAP220. Interestingly, whereas TMF1/ARA160, ELE1/ARA70, ARA54, RAN/ARA24, and PIAS1 were preferentially expressed in epithelial cells, another co-factor, ARA55, was preferentially expressed in stromal cells. Although the changes in levels of these co-activators did not correlate with Gleason score, their occurrence in high-grade prostatic intraepithelial neoplasia, suggests their involvement in initiation (or an early stage) of cancer. In addition, human prostate tumor cell proliferation and colony formation were markedly reduced by ELE1/ATRA70. Together, these findings indicate that changes in levels of expression of AR co-factors may play important, yet different, roles in prostate tumorigenesis

Tuberous sclerosis complex (TSC) is a genetically heterogeneous disease caused by mutations of TSC1 or TSC2 genes. It involves multiple organ systems resulting in mild to lethal hamartoma formation due to gene mutation in the germ line and loss of heterozygosity (LOH) in somatic cells. Hamartin (TSC1) and tuberin (TSC2) are expressed broadly. However, little is known about tissue susceptibility to hamartomas when equal or similar amounts of TSC gene expression are present. In this study, we present a 19-week gestational age fetus with pathological features of TSC, which was confirmed by finding LOH of TSC2 in a cardiac rhabdomyoma. Developmental expression of hamartin and tuberin in the TSC fetus, an age-matched non-TSC fetus, and a 26-week gestational age non-TSC fetus were analyzed by immunohistochemistry. We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues. In general, hamartin and tuberin are mainly expressed in epithelial cells, myocytes, and neural tissues. By comparing the incidence of the hamartomas in early childhood and gene expression in tissues, it appears that tissues with co-expression of hamartin and tuberin are prone to a higher incidence of hamartomas than those expressing only one protein, or two proteins but in different patterns of cellular localization

Gastrointestinal stromal tumor (GIST), a stromal tumor of the gastrointestinal tract defined as CD117 (c-kit)-positive neoplasm, occurs primarily in adults. GIST with CD117 (c-kit) mutation and certain cytogenetic abnormalities is associated with malignancy, though a definite relationship between prognosis and molecular alterations remains to be elucidated. We report the cytologic features of an epithelioid GIST arising in the stomach of a child and metastatic to the liver, and the molecular mutational analysis of both the primary gastric tumor and the liver metastasis. Literature of pediatric GISTs was also reviewed. Fine needle aspiration of the liver metastasis, processed by Ultrafast Papanicolaou stain, showed fragments of cohesive small epithelioid cells with bland oval nuclei and unipolar cytoplasm transected by capillaries. Immunohistochemically, all nodules in the stomach and liver expressed CD117 (c-kit). Interestingly, some of the gastric tumor clusters were uniformly CD34 positive, whereas others were uniformly CD34 negative, suggesting heterogeneity of tumor clones. The presence of neurosecretory granules further subtyped the tumor into gastric autonomic nerve tumor (GANT). Molecular mutational analysis, performed in both the gastric tumor and the liver metastasis, showed no sequence abnormality in exons 9, 11, and 13 of CD117 (c-kit). Cytogenetic study revealed normal karyotype. These features might suggest a different molecular mechanism leading to malignancy in certain GISTs arising in children

The fine-needle aspiration cytologic findings of Wilms' tumor occurring in a 20-yr-old female patient and a 35-yr-old male patient showing blastemal, spindled sarcomatous and rare epithelial components are reported. The male patient had the typical presentation of renal mass with metastasis to lung and pleura, whereas the female patient had an unusual presentation with the tumor originated from the subcapsular nephrogenic zone of the kidney, extending into the liver without invasion into the renal cortex. Cytogenetic analysis of this case identified: 90, XXXX, +2x3-4, -5, -15, -16, -17, -17, i (17)(q10) x2. This finding may represent a genetic change associated with Wilms' tumor of older pediatric and young adult patients. To the best of our knowledge, this case is the sixth case with cytogenetic study and the first case revealing isochromosome 17q of an adult Wilms' tumor

Identifying genes upregulated in lead-resistant cells should give insight into lead toxicity and cellular protective mechanisms and may also result in identification of proteins that may be useful as biomarkers. Glial cells are thought to protect neurons against heavy metals. Rat glioma C6 cells share many properties of normal glial cells. To identify and analyze genes upregulated in a lead-resistant variant, PbR11, suppression subtractive hybridization (SSH) between mRNAs of wild-type and PbR11 cells was performed. Sequencing and database searches identified three genes, thrombospondin-1, heparin sulfate 6-sulfotransferase, and neuropilin-1, which play important roles in angiogenesis and axon growth during development. Two genes, HSP90 and UBA3, are involved in the ubiquitin-proteosome system. One gene was identified as that of a rat endogenous retrovirus and another, 2C9, is a transcript expressed in fos-transformed cells. PbR11 also overexpresses c-fos. Expression of these genes and effects of short-term lead exposure (24 h, up to 600 microM) on their expression in C6 cells was examined. The rat endogenous retrovirus and 2C9 are expressed only in PbR11 cells, and show no expression, either constitutive or lead-induced, in wild-type C6 cells. HSP90 is expressed at low level constitutively in C6 cells, but can be induced in a dose-dependent manner by lead. In contrast, thrombospondin-1 is repressed in a dose-dependent manner by lead. The other genes (HS6ST, neuropilin, and UBA3) show low constitutive expression and are neither upregulated nor downregulated by exposure to lead. We suggest that neuropilin-1, heparin sulfate 6-sulfotransferase, and thrombospondin-1 may be important targets for lead-induced developmental neurotoxicity