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• W1567404006 abstract "To study phenotype-genotype correlations, ErbB/Ras pathway tumors (transgenic for ErbB2, c-Neu, mutants of c-Neu, polyomavirus middle T antigene (PyV-mT), Ras, and bi-transgenic for ErbB2/Neu with ErbB3 and with progesterone receptor) from four different institutions were histopathologically compared with Wnt pathway tumors [transgenes Wnt1, Wnt10b, dominant-negative glycogen synthase kinase 3-β, β-Catenin, and spontaneous mutants of adenomatous polyposis coli gene (Apc)]. ErbB/Ras pathway tumors tend to form solid nodules consisting of poorly differentiated cells with abundant cytoplasm. ErbB/Ras pathway tumors also have scanty stroma and lack myoepithelial or squamous differentiation. In contrast, Wnt pathway tumors exhibit myoepithelial, acinar, or glandular differentiation, and, frequently, combinations of these. Squamous metaplasia is frequent and may include transdifferentiation to epidermal and pilar structures. Most Wnt pathway tumors form caricatures of elongated, branched ductules, and have well-developed stroma, inflammatory infiltrates, and pushing margins. Tumors transgenic for interacting genes such as protein kinase CK2α (casein kinase IIα), and the fibroblast growth factors (Fgf) Int2/Fgf3 or keratinocyte growth factor (Kgf/Fgf7) also have the Wnt pathway phenotype. Because the tumors from the ErbB/Ras and the Wnt pathway are so distinct and can be readily identified using routine hematoxylin and eosin sections, we suggest that pathway pathology is applicable in both basic and clinical cancer research. To study phenotype-genotype correlations, ErbB/Ras pathway tumors (transgenic for ErbB2, c-Neu, mutants of c-Neu, polyomavirus middle T antigene (PyV-mT), Ras, and bi-transgenic for ErbB2/Neu with ErbB3 and with progesterone receptor) from four different institutions were histopathologically compared with Wnt pathway tumors [transgenes Wnt1, Wnt10b, dominant-negative glycogen synthase kinase 3-β, β-Catenin, and spontaneous mutants of adenomatous polyposis coli gene (Apc)]. ErbB/Ras pathway tumors tend to form solid nodules consisting of poorly differentiated cells with abundant cytoplasm. ErbB/Ras pathway tumors also have scanty stroma and lack myoepithelial or squamous differentiation. In contrast, Wnt pathway tumors exhibit myoepithelial, acinar, or glandular differentiation, and, frequently, combinations of these. Squamous metaplasia is frequent and may include transdifferentiation to epidermal and pilar structures. Most Wnt pathway tumors form caricatures of elongated, branched ductules, and have well-developed stroma, inflammatory infiltrates, and pushing margins. Tumors transgenic for interacting genes such as protein kinase CK2α (casein kinase IIα), and the fibroblast growth factors (Fgf) Int2/Fgf3 or keratinocyte growth factor (Kgf/Fgf7) also have the Wnt pathway phenotype. Because the tumors from the ErbB/Ras and the Wnt pathway are so distinct and can be readily identified using routine hematoxylin and eosin sections, we suggest that pathway pathology is applicable in both basic and clinical cancer research. Genetically engineered mice (GEM) have been used extensively to model human breast cancer and to dissect the molecular pathways contributing to tumorigenesis. Most mammary tumors in GEM are different from spontaneous, virus-induced mammary tumors in mice.1Cardiff RD Anver MR Gusterson BA Hennighausen L Jensen RA Merino MJ Rehm S Russo J Tavassoli FA Wakefield LM Ward JM Green JE The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.Oncogene. 2000; 19: 968-988Crossref PubMed Scopus (407) Google Scholar As previously reported, many transgenes in GEM induce tumors with specific, signature histological phenotypes.2Cardiff RD Sinn E Muller W Leder P Transgenic oncogene mice. Tumor phenotype predicts genotype.Am J Pathol. 1991; 139: 495-501PubMed Google Scholar The initial observations were based on the cases collected in one laboratory at the Harvard Medical School. They demonstrated that the Ras, Neu, and Myc transgenes, promoted by the murine mammary tumor virus long terminal repeat (MMTV-LTR), produced signature tumors with small round cells, intermediate cells, and large cells, respectively. These observations suggested that phenotype predicts genotype.2Cardiff RD Sinn E Muller W Leder P Transgenic oncogene mice. Tumor phenotype predicts genotype.Am J Pathol. 1991; 139: 495-501PubMed Google Scholar Subsequent studies have shown that the signature phenotypes for these three genes are similar in different laboratories even with different constructs and different promoters.3Guy CT Webster MA Schaller M Parsons TJ Cardiff RD Muller WJ Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.Proc Natl Acad Sci USA. 1992; 89: 10578-10582Crossref PubMed Scopus (1010) Google Scholar, 4Siegel PM Dankort DL Hardy WR Muller WJ Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors.Mol Cell Biol. 1994; 14: 7068-7077Crossref PubMed Scopus (187) Google Scholar, 5Andrechek ER Hardy WR Siegel PM Rudnicki MA Cardiff RD Muller WJ Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis.Proc Natl Acad Sci USA. 2000; 97: 3444-3449Crossref PubMed Scopus (189) Google ScholarSince the initial studies, the University of California, Davis Mutant Mouse Pathology Archives have accumulated more than 3000 GEM mammary tumors that now include a sufficient variety of GEM to allow comparisons of tumors within specific signal transduction pathways. We have, therefore, undertaken a systematic study of the morphology of ErbB/Ras pathway tumors as compared with Wnt pathway tumors.The Wnt1 gene is one of the most commonly induced genes in mice after the insertional activation by MMTV (murine mammary tumor virus).6Callahan R MMTV-induced mutations in mouse mammary tumors: their potential relevance to human breast cancer.Breast Cancer Res Treat. 1996; 39: 33-44Crossref PubMed Scopus (60) Google Scholar The Wnt1 gene was first named “Int1”, or MMTV integration site 1, until the activated gene was found to be the homologue of the Drosophila wingless gene.7Nusse R Brown A Papkoff J Scambler P Shackleford G McMahon A Moon R Varmus H A new nomenclature for int-1 and related genes: the Wnt gene family.Cell. 1991; 64: 231Abstract Full Text PDF PubMed Scopus (245) Google Scholar The second gene commonly activated by MMTV insertion is known as Int2 but has turned out to be a member of the Fgf family, Fgf3.8Dickson C Peters G Potential oncogene product related to growth factors.Nature. 1987; 326: 833Crossref PubMed Scopus (218) Google Scholar Although members of the Wnt and the Fgf families have been implicated in human cancer, neither has been frequently found in association with human breast cancer. A number of transgenic, mutant, and knockout mice have now been developed that involve the Wnt pathway.9Lee FS Lane TF Kuo A Shackleford GM Leder P Insertional mutagenesis identifies a member of the Wnt gene family as a candidate oncogene in the mammary epithelium of int-2/Fgf-3 transgenic mice.Proc Natl Acad Sci USA. 1995; 92: 2268-2272Crossref PubMed Scopus (107) Google Scholar, 10Lane TF Leder P Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice.Oncogene. 1997; 15: 2133-2144Crossref PubMed Scopus (119) Google Scholar, 11Landesman-Bollag E Romieu-Mourez R Song DH Sonenshein GE Cardiff RD Seldin DC Protein kinase CK2 in mammary gland tumorigenesis.Oncogene. 2001; 20: 3247-3257Crossref PubMed Scopus (267) Google Scholar, 12Michaelson JS Leder P Beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland.Oncogene. 2001; 20: 5093-5099Crossref PubMed Scopus (149) Google Scholar Tumors in these GEM resemble the classical MMTV-induced tumors13Dunn T Morphology of mammary tumors in mice.in: Homburger F The Physiopathology of Cancer. Hoeber-Harper, New York1959: 38-84Google Scholar suggesting that activation of the same gene by different mechanisms results in the same type of tumor. The MMTV-induced tumors have characteristic histological patterns that are not generally found in human breast cancer.1Cardiff RD Anver MR Gusterson BA Hennighausen L Jensen RA Merino MJ Rehm S Russo J Tavassoli FA Wakefield LM Ward JM Green JE The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.Oncogene. 2000; 19: 968-988Crossref PubMed Scopus (407) Google ScholarInterestingly, Wnt1 GEM infected with MMTV were found to have insertional activation of Fgf8, Fgf4, and Fgf3 and GEM transgenic for Fgf3 infected with MMTV were found to have activation of Wnt10b, suggesting cooperativity between Fgf and Wnt signaling.6Callahan R MMTV-induced mutations in mouse mammary tumors: their potential relevance to human breast cancer.Breast Cancer Res Treat. 1996; 39: 33-44Crossref PubMed Scopus (60) Google Scholar, 9Lee FS Lane TF Kuo A Shackleford GM Leder P Insertional mutagenesis identifies a member of the Wnt gene family as a candidate oncogene in the mammary epithelium of int-2/Fgf-3 transgenic mice.Proc Natl Acad Sci USA. 1995; 92: 2268-2272Crossref PubMed Scopus (107) Google Scholar, 14Kapoun AM Shackleford GM Preferential activation of Fgf8 by proviral insertion in mammary tumors of Wnt1 transgenic mice.Oncogene. 1997; 14: 2985-2989Crossref PubMed Scopus (24) Google ScholarOn the other hand, tumors arising in ErbB2 GEM have a completely different histopathological pattern that does not resemble the MMTV-induced tumors1Cardiff RD Anver MR Gusterson BA Hennighausen L Jensen RA Merino MJ Rehm S Russo J Tavassoli FA Wakefield LM Ward JM Green JE The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.Oncogene. 2000; 19: 968-988Crossref PubMed Scopus (407) Google Scholar but rather do resemble some human tumors.2Cardiff RD Sinn E Muller W Leder P Transgenic oncogene mice. Tumor phenotype predicts genotype.Am J Pathol. 1991; 139: 495-501PubMed Google Scholar ErbB2 is a member of the epidermal growth factor receptor family and is amplified in ∼25% of human breast cancer.15Barnes DM Bartkova J Camplejohn RS Gullick WJ Smith PJ Millis RR Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance?.Eur J Cancer. 1992; 28: 644-648Abstract Full Text PDF PubMed Scopus (116) Google Scholar Neu is an activated rat homologue of ErbB2.16Bargmann CI Hung MC Weinberg RA The neu oncogene encodes an epidermal growth factor receptor-related protein.Nature. 1986; 319: 226-230Crossref PubMed Scopus (931) Google Scholar When either c-ErbB2 or Neu is expressed behind the highly mammary selective MMTV-LTR promotor, a signature solid nodular tumor is generally produced.3Guy CT Webster MA Schaller M Parsons TJ Cardiff RD Muller WJ Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.Proc Natl Acad Sci USA. 1992; 89: 10578-10582Crossref PubMed Scopus (1010) Google Scholar, 4Siegel PM Dankort DL Hardy WR Muller WJ Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors.Mol Cell Biol. 1994; 14: 7068-7077Crossref PubMed Scopus (187) Google Scholar, 17Webster MA Muller WJ Mammary tumorigenesis and metastasis in transgenic mice.Semin Cancer Biol. 1994; 5: 69-76PubMed Google Scholar Although some morphological differences may separate the Ras tumors from the Neu tumors, their phenotypes overlap to a significant degree.2Cardiff RD Sinn E Muller W Leder P Transgenic oncogene mice. Tumor phenotype predicts genotype.Am J Pathol. 1991; 139: 495-501PubMed Google Scholar, 18Cardiff RD Wellings SR The comparative pathology of human and mouse mammary glands.J Mammary Gland Biol Neoplasia. 1999; 4: 105-122Crossref PubMed Scopus (185) Google Scholar Because polyoma virus middle T (PyV-mT) imitates ErbB2, it is considered a molecular surrogate for ErbB2.19Webster MA Hutchinson JN Rauh MJ Muthuswamy SK Anton M Tortorice CG Cardiff RD Graham FL Hassell JA Muller WJ Requirement for both Shc and phosphatidylinositol 3′ kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.Mol Cell Biol. 1998; 18: 2344-2359Crossref PubMed Scopus (178) Google Scholar PyV-mT protein also induces solid tumors.19Webster MA Hutchinson JN Rauh MJ Muthuswamy SK Anton M Tortorice CG Cardiff RD Graham FL Hassell JA Muller WJ Requirement for both Shc and phosphatidylinositol 3′ kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.Mol Cell Biol. 1998; 18: 2344-2359Crossref PubMed Scopus (178) Google ScholarWe now report that tumors involving other members of these two pathways in GEM share one or more morphological characteristics with the better known members of the Wnt or ErbB/Ras pathways. We describe here the morphological features shared by five members of the Wnt pathway and three cooperating genes as compared to those shared by six members of the ErbB2/Ras family. These studies extend the principle that phenotype predicts genotype to demonstrate that alterations in structure and function induced by genes can also be classified by the signal transduction pathway. Because these mouse mammary tumors have such different and easily identified morphologies, they belong to distinct taxonomic groups that are related to the pathways and we suggest the term “pathway pathology” to indicate the shared morphology within each pathway.Materials and MethodsMiceThe samples used in this study came from murine tumors that were sent to us as a part of studies of oncogene tumorigenesis in transgenic mice initiated by our collaborators. All transgenes used here were under the control of an MMTV-LTR promotor except the PR− transgenics, created by using a binary system, as described previously.20Shyamala G Yang X Silberstein G Barcellos-Hoff MH Dale E Transgenic mice carrying an imbalance in the native ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands.Proc Natl Acad Sci USA. 1998; 95: 696-701Crossref PubMed Scopus (171) Google Scholar, 21Shyamala G Yang X Cardiff RD Dale E Impact of progesterone receptor on cell-fate decisions during mammary gland development.Proc Natl Acad Sci USA. 2000; 97: 3044-3049Crossref PubMed Scopus (116) Google Scholar All transgenic mice were bred in the FVB background strain. In addition, spontaneous Min mutants of the adenomatous polyposis coli (ApcMin) gene in C57/BL/6J and (AKRx C57/BL/6J Min/+) F1 and N2 background were studied. Three of the six ApcMin mice were treated with ethylnitrosourea, a chemical carcinogen.22Moser AR Mattes EM Dove WF Lindstrom MJ Haag JD Gould MN ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias.Proc Natl Acad Sci USA. 1993; 90: 8977-8981Crossref PubMed Scopus (183) Google ScholarThe animals were inspected for tumors at least once a week. Animals with tumors were necropsied between 1991 and 2001, and samples of tumors, adjacent mammary gland, and other tissues were fixed in neutral buffered 4% formalin or in Optimal Fix (American Master Tech Scientific, Inc., Lodi, CA), embedded in paraffin, cut into 4-μm sections, and stained with Mayer's hematoxylin and eosin (H&E). Animal data, gross description, slides, and, in most cases, paraffin blocks were stored at the University of California Davis Mutant Mouse Pathology Laboratory.TumorsErbB/Ras PathwayRepresentative mouse mammary tumors (n = 107) transgenic for the ErbB/Ras pathway were selected for this study. The transgenes were ErbB2/Neu,3Guy CT Webster MA Schaller M Parsons TJ Cardiff RD Muller WJ Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.Proc Natl Acad Sci USA. 1992; 89: 10578-10582Crossref PubMed Scopus (1010) Google Scholar, 23Muller WJ Sinn E Pattengale PK Wallace R Leder P Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene.Cell. 1988; 54: 105-115Abstract Full Text PDF PubMed Scopus (928) Google Scholar, 24Guy CT Cardiff RD Muller WJ Activated neu induces rapid tumor progression.J Biol Chem. 1996; 271: 7673-7678Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Neu mutants NDL1-4 and NDL2-5,4Siegel PM Dankort DL Hardy WR Muller WJ Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors.Mol Cell Biol. 1994; 14: 7068-7077Crossref PubMed Scopus (187) Google Scholar as well as transgenic crosses: ErbB2 with ErbB3 (Gillgrass and Muller, McMaster University, unpublished results), or with progesterone receptor α (n = 4) or β (n = 1) (G Shyamala, University of California, Berkeley, unpublished results). In addition, PyV-mT,19Webster MA Hutchinson JN Rauh MJ Muthuswamy SK Anton M Tortorice CG Cardiff RD Graham FL Hassell JA Muller WJ Requirement for both Shc and phosphatidylinositol 3′ kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis.Mol Cell Biol. 1998; 18: 2344-2359Crossref PubMed Scopus (178) Google Scholar, 25Guy CT Cardiff RD Muller WJ Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease.Mol Cell Biol. 1992; 12: 954-961Crossref PubMed Scopus (1237) Google Scholar, 26Maglione JE Moghanaki D Young LJ Manner CK Ellies LG Joseph SO Nicholson B Cardiff RD MacLeod CL Transgenic polyoma middle-T mice model premalignant mammary disease.Cancer Res. 2001; 61: 8298-8305PubMed Google Scholar and Ras2Cardiff RD Sinn E Muller W Leder P Transgenic oncogene mice. Tumor phenotype predicts genotype.Am J Pathol. 1991; 139: 495-501PubMed Google Scholar tumors were examined.Wnt PathwayTumors (n = 112) with one transgene or mutation activating the Wnt pathway were used. Bitransgenic tumors were not included because of the complexity of phenotypes in the Wnt pathway. The transgenes were Wnt1,12Michaelson JS Leder P Beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland.Oncogene. 2001; 20: 5093-5099Crossref PubMed Scopus (149) Google Scholar Wnt10b,10Lane TF Leder P Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice.Oncogene. 1997; 15: 2133-2144Crossref PubMed Scopus (119) Google Scholar protein kinase CK2α (formerly casein kinase IIa),11Landesman-Bollag E Romieu-Mourez R Song DH Sonenshein GE Cardiff RD Seldin DC Protein kinase CK2 in mammary gland tumorigenesis.Oncogene. 2001; 20: 3247-3257Crossref PubMed Scopus (267) Google Scholar β-Catenin,12Michaelson JS Leder P Beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland.Oncogene. 2001; 20: 5093-5099Crossref PubMed Scopus (149) Google Scholar dominant-negative mutant of glycogen synthase kinase 3-b (dnGSK3β) (D. C. Seldin, unpublished results). In addition, ApcMin mutants27Moser AR Hegge LF Cardiff RD Genetic background affects susceptibility to mammary hyperplasias and carcinomas in Apc(min)/+ mice.Cancer Res. 2001; 61: 3480-3485PubMed Google Scholar were studied.Int2 PathwayNinety tumors transgenic for Int2/Fgf328Muller WJ Lee FS Dickson C Peters G Pattengale P Leder P The int-2 gene product acts as an epithelial growth factor in transgenic mice.EMBO J. 1990; 9: 907-913Crossref PubMed Scopus (191) Google Scholar, 29Kwan H Pecenka V Tsukamoto A Parslow TG Guzman R Lin TP Muller WJ Lee FS Leder P Varmus HE Transgenes expressing the Wnt-1 and int-2 proto-oncogenes cooperate during mammary carcinogenesis in doubly transgenic mice.Mol Cell Biol. 1992; 12: 147-154Crossref PubMed Scopus (112) Google Scholar or for keratinocyte growth factor (Kgf/Fgf7)30Kitsberg DI Leder P Keratinocyte growth factor induces mammary and prostatic hyperplasia and mammary adenocarcinoma in transgenic mice.Oncogene. 1996; 13: 2507-2515PubMed Google Scholar were studied.The tumors were initially classified using the taxonomy recommended by the Annapolis Pathology Panel.1Cardiff RD Anver MR Gusterson BA Hennighausen L Jensen RA Merino MJ Rehm S Russo J Tavassoli FA Wakefield LM Ward JM Green JE The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.Oncogene. 2000; 19: 968-988Crossref PubMed Scopus (407) Google Scholar However, the remarkable phenotypes in the Wnt pathway tumors required the development of new taxonomic groups and terms (section results). Images were captured with ×10 and ×20 objectives using a Carl Zeiss (Thornwood, NY) Axiocam camera and were processed using Adobe Photoshop (Adobe Systems Incorporated) software.Immunohistochemistry (IHC)IHC was performed on 35 tumors transgenic for ErbB2, Neu mutants, and PyV-mT, and on 40 tumors transgenic for the Wnt pathway to assess myoepithelial differentiation, further on 5 tumors transgenic for the Wnt pathway to demonstrate ductular architecture, and on skin and 5 mammary pilar tumors to study pilar differentiation. Four-μm paraffin sections were placed onto Superfrost/Plus slides (Fisher Scientific, Pittsburgh, PA), deparaffinized, and cleared. IHC was performed after inhibition of endogenous peroxidase activity in a solution of 3% hydrogen peroxide (H2O2) in methanol and hydration in graded alcohol to distilled water. Before antibody incubations, antigen retrieval was performed by high temperature (microwave) incubation in 0.01 mol/L of citric acid buffer (pH 6.0) for 3 × 4 minutes. Slides were allowed to cool for 10 minutes in citric acid buffer then transferred to phosphate-buffered saline (pH 7.4) (2 × 5 minutes each). Ten percent normal horse serum (Vector Laboratories, Burlingame, CA) was applied to sections and incubated for 20 minutes in a humidified chamber at room temperature.IHC for smooth muscle actin (SMA) was performed using a 1:1000 diluted mouse monoclonal primary antibody (Sigma, St. Louis, MO). IHC for hard (hair) keratin was performed using a 1:20 diluted cell culture supernatant with the mouse monoclonal primary antibody AE-1331Lynch MH O'Guin WM Hardy C Mak L Sun TT Acidic and basic hair/nail (“hard”) keratins: their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to “soft” keratins.J Cell Biol. 1986; 103: 2593-2606Crossref PubMed Scopus (302) Google Scholar (a kind gift from T.-T. Sun, New York University). The Animal Research Kit (DAKO, Carpinteria, CA) with peroxidase was used as amplification system according to the manufacturer's instructions.To exclude SMA-positive myofibroblasts, all 12 questionable SMA-positive ErbB/Ras pathway tumors, two adenomyoepitheliomas, and 5 spindle cell tumors were stained for cytokeratin 14 (CK14). Staining for cytokeratin 8 (CK8) was performed to illustrate the ductular organization of Wnt pathway tumors. We used 1:200 (CK14) and 1:300 (CK8) diluted polyclonal sheep primary antibodies (Binding Site, San Diego, CA). Slides were covered with primary antibody solution and were incubated overnight at room temperature. The Vectastain ABC Elite Kit (Vector Laboratories) was used as amplification system according to the manufacturer's instructions. Slides were counterstained in Mayer's hematoxylin, dehydrated, cleared, and coverslipped. Negative control slides were run without primary antibody. Control slides known to be positive for each antibody were incorporated into each run.ResultsErbB/Ras Pathway TumorsErbB2 and Ras transgenic mammary tumors have recognizable signature phenotypes as previously described.1Cardiff RD Anver MR Gusterson BA Hennighausen L Jensen RA Merino MJ Rehm S Russo J Tavassoli FA Wakefield LM Ward JM Green JE The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.Oncogene. 2000; 19: 968-988Crossref PubMed Scopus (407) Google Scholar Ras tumors consist of uniform cells with abundant eosinophilic cytoplasm and small ovoid nucleus with dense chromatin structure. ErbB2/Neu tumor cells are larger than Ras tumor cells, and have larger nuclei and paler but abundant cytoplasm (Figure 1E). ErbB2/Neu transgenic tumors are solid and nodular (Table 1). Solid ErbB/Ras pathway tumors (Figure 1, A and E) have characteristic concentric zones of cell populations: I, one to two peripheral layers of pallisading cells; II, several, more internal layers of larger cells with larger nuclei and more open chromatin structure (vesicular in the ErbB2/Neu tumors); and III, small, tightly packed central cells with smaller, elongated nuclei and less cytoplasm than in the other zones. Some tumors have central necrosis surrounded by bigger tumor cells than the zone III type cells. PyV-mT (Figure 1C) and Ras transgenic tumors have more variable phenotypes than ErbB2 tumors (Table 1). Some solid PyV-mT tumors have minor components of glandular differentiation or cystic spaces. Although ErbB/Ras pathway tumors can have histological types other than solid (Table 1), they all contain solid components. With few exceptions, ErbB/Ras pathway tumors share common morphological characteristics.Table 1Histological Types of ErbB/Ras Pathway Transgenic TumorsTransgeneAcinarGlandularPapillarySolidAdenosquamousPilarType PMyoepithelialErbB2/Neu (n = 12)001110000activated Neu (n = 5)00050000Neu mutants (n = 25)000250000ErbB2 and PR (n = 5)00050000ErbB2 and ErbB3 (n = 5)00050000PyV-mt (n = 49)285292210Ras (n = 6)10050000(n = 107)386852210(100%)(3%)(7%)(6%)(79%)(2%)(2%)(1%)(0%) Open table in a new tab The signature characteristics of the ErbB/Ras pathway tumors (Table 3) are: solid pattern (Table 1; Figure 1, A and E), scanty stroma (Figure 1; A, C, and E), invasive growth (Figure 1C), no myoepithelium (Figure 1E), and no squamous metaplasia (Figure 1; A, C, and E). The PyV-mT tumors tend to have more stroma than Ras and ErbB2 tumors. Except for one tumor, ErbB/Ras pathway tumors do not have any evidence of milk or lipid secretion, even when the adjacent mammary gland is lactating. The connective tissue adjacent to the tumor has either no response or is edematous, but not fibrous (Figure 1E). Inflammatory infiltrates are limited to necrotic zones.Table 3Morphologic Criteria to Distinguish ErbB/Ras from Wnt Pathway TumorsCriterionErbB/Ras pathwayWnt pathwayHistological patternSolidBranched ductules/acinar componentKeratinizationRarely presentFrequently presentMyoepitheliumNot presentFrequently present;*While myoepithelial spindle cell tumors and adenomyoepitheliomas represent only 15% of the Wnt pathway tumors, a basal myoepithelial layer is observed in more than 50% of the Wnt pathway tumors.StromaScantyDenseInflammatory infiltratesPresent only in necrosisFrequently present* While myoepithelial spindle cell tumors and adenomyoepitheliomas represent only 15% of the Wnt pathway tumors, a basal myoepithelial layer is observed in more than 50% of the Wnt pathway tumors. Open table in a new tab The ErbB2/Neu phenotype is consistently found in combinations of ErbB2/c-Neu transgenes with progesterone receptor or ErbB3 transgenes.Wnt Pathway TumorsMammary tumors induced by mutations in genes of the canonical Wnt pathway, or of the Wnt pathway interactors CK2a, Int2 (Fgf-3), or Kgf (Fgf-7) (in the following referred to as Wnt pathway tumors) exhibit a variety of morphological patterns. Despite the variety of histological types (Table 2), these transgenic tumors have common histological characteristics, which are different from the ErbB/Ras pathway phenotype (Table 3). The key features of Wnt pathway tumors are branched ductular architecture (Figure 2, A and B), dense stroma with lymphocytic infiltrates (Figure 1, B and D, and Figure 2, A to D), and differentiation into acinar (Figure 1D), squamous (Figure 1, Figure 2), and myoepithelial (Figure 1F and Figure 2, E and F) components. Each of these characteristics was found in more than 50% of the Wnt pathway tumors studied, and each Wnt pathway tumor had at least one of these characteristics.Table 2Histological Types of Wnt Pathway and CK2α and Fgf Transgenic TumorsTransgeneAcinarGlandularPapillarySolidAdenosquamousPilarType PMyoepithelialWnt1 (n = 7)00100060Wnt10b (n = 23)74110190CK2α (n = 29)216018110dnGSK-3β (n = 36)168021117Apc (n = 6)00000600β-Catenin (n = 11)22500110Int2 (n = 34)66705712Kgf (n = 56)21061119512(n = 202)20293429532431(100%)(10%)(14%)(17%)(1%)(4%)(27%)(12%)(15%) Open table in a new tab Figure 2Characteristics of Wnt pathway tumors: Ductular architecture (A, B) with glandular (B), papillary (C), pilar (D), and myoepithelial differentiation (E, F), and dense stroma with lymphocytic infiltrates (A–D). A: Type P tumor. Note the well-differentiated branching neoplastic ductules (transgene: Wnt10b). B: Type P tumor with glandular differentiation (transgene: Wnt1). C: Papillary tumor with micropapillary components. The ductular architecture is less prominent than in type P tumors (transgene: CK2a). D: Pilar tumor with squamous metaplasia and ghost cells (G) embedded in fibrous stroma with moderate inflammatory infiltrates. Staining with antibody AE-13 shows that expression of hair keratin in viable cells is limited to few single cells (arrow) (transgene: Int2). E: Myoepithelial differentiation in a spindle cell tumor (transgene: CK2a). F: Lung metastasis of a glandular mammary tumor with secretory activity (S) and maintained myoepithelium. In mice, maintained myoepithelium does not exclude tumor emboli or metastasis (transgene: Kgf). All photographs were taken with a ×10 or a ×20 objective, the exact scale is given in" @default.
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• W1567404006 date "2002-09-01" @default.
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• W1567404006 title "Pathway Pathology" @default.
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