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Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators.
Owens P, Pickup MW, Novitskiy SV, Chytil A, Gorska AE, Aakre ME, West J, Moses HL
(2012) Proc Natl Acad Sci U S A 109: 2814-9
MeSH Terms: Animals, Antigens, Polyomavirus Transforming, Bone Morphogenetic Protein Receptors, Type II, Cell Movement, Cell Proliferation, Chemokines, Disease Progression, Female, Humans, Inflammation, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mammary Tumor Virus, Mouse, Mice, Myeloid Cells, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Paracrine Communication, Signal Transduction, Tumor Microenvironment
Show Abstract · Added March 7, 2014
Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in carcinoma cells as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have tumor suppressive and promoting effects. We sought to determine whether disruption of the BMP receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen. Mice expressing Polyoma middle T antigen under the mouse mammary tumor virus promoter were combined with mice that have doxycycline-inducible expression of a dominant-negative (DN) BMPR2. We did not observe any differences in tumor latency. However, mice expressing the BMPR2-DN had a fivefold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN-expressing tumor cells had higher rates of proliferation. We also identified unique changes in inflammatory cells and secreted chemokines/cytokines that accompanied BMPR2-DN-expressing tumors. By immunohistochemistry, it was found that BMPR2-DN primary tumors and metastases had an altered reactive stroma, indicating specific changes in the tumor microenvironment. Among the changes we discovered were increased myeloid derived suppressor cells and the chemokine CCL9. BMP was shown to directly regulate CCL9 expression. We conclude that BMPR2 has tumor-suppressive function in mammary epithelia and microenvironment and that disruption can accelerate mammary carcinoma metastases.
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1 Members
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21 MeSH Terms
ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis.
Cook RS, Garrett JT, Sánchez V, Stanford JC, Young C, Chakrabarty A, Rinehart C, Zhang Y, Wu Y, Greenberger L, Horak ID, Arteaga CL
(2011) Cancer Res 71: 3941-51
MeSH Terms: Animals, Breast Neoplasms, Cell Growth Processes, Cell Line, Tumor, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Humans, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Oligonucleotides, Antisense, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-3, Signal Transduction
Show Abstract · Added March 5, 2014
The ErbB receptor family member ErbB3 has been implicated in breast cancer growth, but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt as well as tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), and ErbB3, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. In this article, we report that ErbB3 is critical for PI3K/Akt-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth, and pulmonary metastasis. Furthermore, EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no toxicity in the mouse model. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.
1 Communities
2 Members
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18 MeSH Terms
Loss of one Tgfbr2 allele in fibroblasts promotes metastasis in MMTV: polyoma middle T transgenic and transplant mouse models of mammary tumor progression.
Fang WB, Jokar I, Chytil A, Moses HL, Abel T, Cheng N
(2011) Clin Exp Metastasis 28: 351-66
MeSH Terms: Alleles, Animals, Antigens, Polyomavirus Transforming, Disease Models, Animal, Disease Progression, Female, Fibroblasts, Male, Mammary Neoplasms, Animal, Mammary Tumor Virus, Mouse, Mice, Mice, Nude, Mice, Transgenic, Neoplasm Metastasis, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Tumor Cells, Cultured
Show Abstract · Added March 10, 2014
Accumulation of fibroblasts is a phenomenon that significantly correlates with formation of aggressive cancers. While studies have shown that the TGF-β signaling pathway is an important regulator of fibroblast activation, the functional contribution of TGF-β signaling in fibroblasts during multi-step tumor progression remains largely unclear. In previous studies, we used a sub-renal capsule transplantation model to demonstrate that homozygous knockout of the Tgfbr2 gene (Tgbr2(FspKO)) enhanced mammary tumor growth and metastasis. Here, we show for the first time a significant role for loss of one Tgfbr2 allele during multi-step mammary tumor progression. Heterozygous deletion of Tgfbr2 in stromal cells in MMTV-PyVmT transgenic mice (PyVmT/Tgfbr2(hetFspKO) mice) resulted in earlier tumor formation and increased stromal cell accumulation. In contrast to previous studies of Tgbr2(FspKO) fibroblasts, Tgfbr2(hetFspKO) fibroblasts did not significantly increase tumor growth, but enhanced lung metastasis in PyVmT transgenic mice and in co-transplantation studies with PyVmT mammary carcinoma cells. Furthermore, Tgfbr2(hetFspKO) fibroblasts enhanced mammary carcinoma cell invasiveness associated with expression of inflammatory cytokines including CXCL12 and CCL2. Analyses of Tgbr2(FspKO) and Tgfbr2(hetFspKO) fibroblasts revealed differences in the expression of factors associated with metastatic spread, indicating potential differences in the mechanism of action between homozygous and heterozygous deletion of Tgfbr2 in stromal cells. In summary, these studies demonstrate for the first time that loss of one Tgfbr2 allele in fibroblasts enhances mammary metastases in a multi-step model of tumor progression, and demonstrate the importance of clarifying the functional contribution of genetic alterations in stromal cells in breast cancer progression.
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2 Members
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18 MeSH Terms
Rapid extravasation and establishment of breast cancer micrometastases in the liver microenvironment.
Martin MD, Kremers GJ, Short KW, Rocheleau JV, Xu L, Piston DW, Matrisian LM, Gorden DL
(2010) Mol Cancer Res 8: 1319-27
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Disease Models, Animal, Female, Liver Neoplasms, Experimental, Lung Neoplasms, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Retroviridae Infections, Tumor Microenvironment, Tumor Virus Infections
Show Abstract · Added December 5, 2013
To examine the interplay between tumor cells and the microenvironment during early breast cancer metastasis, we developed a technique for ex vivo imaging of murine tissue explants using two-photon microscopy. Cancer cells in the liver and the lung were compared by imaging both organs at specific time points after the injection of the same polyomavirus middle T-initiated murine mammary tumor cell line. Extravasation was greatly reduced in the lung compared with the liver, with 56% of tumor cells in the liver having extravasated by 24 hours, compared with only 22% of tumor cells in the lung that have extravasated. In the liver, imaged cells continually transitioned from an intravascular location to an extravascular site, whereas in the lung, extravasation rates slowed after 6 hours. Within the liver microenvironment, the average size of the imaged micrometastatic lesions increased 4-fold between days 5 and 12. Histologic analysis of these lesions determined that by day 12, the micrometastases were heterogeneous, consisting of both tumor cells and von Willebrand factor-positive endothelial cells. Further analysis with intravenously administered lectin indicated that vessels within the micrometastatic tumor foci were patent by day 12. These data present the use of two-photon microscopy to directly compare extravasation times in metastatic sites using the same tumor cell line and highlight the differences in early events and metastatic patterns between two important secondary sites of breast cancer progression with implications for future therapy.
2 Communities
2 Members
0 Resources
13 MeSH Terms
Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component.
Corsino PE, Davis BJ, Nørgaard PH, Parker NN, Law M, Dunn W, Law BK
(2008) Neoplasia 10: 1240-52
MeSH Terms: Animals, Breast Neoplasms, Cadherins, Catenins, Cell Adhesion Molecules, Cell Line, Tumor, Cyclin D1, Cyclin-Dependent Kinase 2, Female, Humans, Immunoblotting, Immunohistochemistry, Intermediate Filament Proteins, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Metalloproteins, Mice, Mice, Transgenic, Microscopy, Fluorescence, Neoplasm Invasiveness, Nerve Tissue Proteins, Nestin, Phosphoproteins, Protein Transport, Stress Fibers, Zyxin, beta Catenin
Show Abstract · Added April 24, 2015
The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2) transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, alpha smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and beta-catenin and p120(ctn) localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, beta-catenin, and p120(ctn) to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.
1 Communities
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27 MeSH Terms
Establishment and quantitative imaging of a 3D lung organotypic model of mammary tumor outgrowth.
Martin MD, Fingleton B, Lynch CC, Wells S, McIntyre JO, Piston DW, Matrisian LM
(2008) Clin Exp Metastasis 25: 877-85
MeSH Terms: Animals, Coculture Techniques, Diagnostic Imaging, Disease Models, Animal, Disease Progression, Female, Flow Cytometry, Green Fluorescent Proteins, Imaging, Three-Dimensional, Immunoenzyme Techniques, Lung Neoplasms, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Microscopy, Confocal, Organ Culture Techniques, Tumor Cells, Cultured
Show Abstract · Added January 17, 2014
The lung is the second most common site of metastatic spread in breast cancer and experimental evidence has been provided in many systems for the importance of an organ-specific microenvironment in the development of metastasis. To better understand the interaction between tumor and host cells in this important secondary site, we have developed a 3D in vitro organotypic model of breast tumor metastatic growth in the lung. In our model, cells isolated from mouse lungs are placed in a collagen sponge to serve as a scaffold and co-cultured with a green fluorescent protein-labeled polyoma virus middle T antigen (PyVT) mammary tumor cell line. Analysis of the co-culture system was performed using flow cytometry to determine the relative constitution of the co-cultures over time. This analysis determined that the cultures consisted of viable lung and breast cancer cells over a 5-day period. Confocal microscopy was then used to perform live cell imaging of the co-cultures over time. Our studies determined that host lung cells influence the ability of tumor cells to grow, as the presence of lung parenchyma positively affected the proliferation of the mammary tumor cells in culture. In summary, we have developed a novel in vitro model of breast tumor cells in a common metastatic site that can be used to study tumor/host interactions in an important microenvironment.
1 Communities
4 Members
0 Resources
20 MeSH Terms
Effects of BRCA1 transgene expression on murine mammary gland development and mutagen-induced mammary neoplasia.
Hoshino A, Yee CJ, Campbell M, Woltjer RL, Townsend RL, van der Meer R, Shyr Y, Holt JT, Moses HL, Jensen RA
(2007) Int J Biol Sci 3: 281-91
MeSH Terms: 9,10-Dimethyl-1,2-benzanthracene, Animals, BRCA1 Protein, Carcinogens, Female, Gene Expression, Gene Transfer Techniques, Genes, BRCA1, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Inbred Strains, Mice, Transgenic, Pregnancy
Show Abstract · Added February 17, 2014
To characterize the role of BRCA1 in mammary gland development and tumor suppression, a transgenic mouse model of BRCA1 overexpression was developed. Using the mouse mammary tumor virus (MMTV) promoter/enhancer, transgenic mice expressing human BRCA1 or select mutant controls were generated. Transgenic animals examined during adolescence were shown to express the human transgene in their mammary glands. The mammary glands of 13-week-old virgin homozygous MMTV-BRCA1 mice presented the morphology of moderately increased lobulo-alveolar development. The mammary ductal trees of both hemizygous and homozygous MMTV-BRCA1t340 were similar to those of control non-transgenic littermates. Interestingly, both hemi- and homozygous mice expressing a splice variant of BRCA1 lacking the N-terminal RING finger domain (MMTV-BRCA1sv) exhibited marked mammary lobulo-alveolar development, particularly terminal end bud proliferation. Morphometric analyses of mammary gland whole mount preparations were used to measure epithelial staining indices of ~35% for homozygous MMTV-BRCA1 mice and ~60% for both hemizygous and homozygous MMTV-BRCA1sv mice versus ~25% for non-transgenic mice. Homozygous MMTV-BRCA1 mice showed delayed development of tumors when challenged with 7,12 dimethylbenzanthracene (DMBA), relative to non-transgenic and homozygous BRCA1t340 expressing mice. In contrast, homozygous MMTV-BRCA1sv transgenic animals were sensitized to DMBA treatment and exhibited a very rapid onset of mammary tumor development and accelerated mortality. MMTV-BRCA1 effects on mortality were restricted to DMBA-induced tumors of the mammary gland. These results demonstrate in vivo roles for BRCA1 in both mammary gland development and in tumor suppression against mutagen-induced mammary gland neoplasia.
1 Communities
1 Members
0 Resources
15 MeSH Terms
Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression.
Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL
(2007) J Clin Invest 117: 1305-13
MeSH Terms: Animals, Antibodies, Blocking, Antigens, Polyomavirus Transforming, Cell Line, Tumor, Female, Humans, Lung Neoplasms, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Neoplasms, Radiation-Induced, Neoplastic Cells, Circulating, Retroviridae Infections, Signal Transduction, Transforming Growth Factor beta, Tumor Virus Infections
Show Abstract · Added February 17, 2014
We investigated whether TGF-beta induced by anticancer therapies accelerates tumor progression. Using the MMTV/PyVmT transgenic model of metastatic breast cancer, we show that administration of ionizing radiation or doxorubicin caused increased circulating levels of TGF-beta1 as well as increased circulating tumor cells and lung metastases. These effects were abrogated by administration of a neutralizing pan-TGF-beta antibody. Circulating polyomavirus middle T antigen-expressing tumor cells did not grow ex vivo in the presence of the TGF-beta antibody, suggesting autocrine TGF-beta is a survival signal in these cells. Radiation failed to enhance lung metastases in mice bearing tumors that lack the type II TGF-beta receptor, suggesting that the increase in metastases was due, at least in part, to a direct effect of TGF-beta on the cancer cells. These data implicate TGF-beta induced by anticancer therapy as a pro-metastatic signal in tumor cells and provide a rationale for the simultaneous use of these therapies in combination with TGF-beta inhibitors.
0 Communities
3 Members
0 Resources
17 MeSH Terms
Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression.
Corsino P, Davis B, Law M, Chytil A, Forrester E, Nørgaard P, Teoh N, Law B
(2007) Cancer Res 67: 3135-44
MeSH Terms: Animals, Cyclin D1, Cyclin-Dependent Kinase 2, Disease Progression, Enzyme Activation, Female, Fibroblasts, Hepatocyte Growth Factor, Hyperplasia, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Promoter Regions, Genetic, Recombinant Fusion Proteins, Retinoblastoma Protein, Retinoblastoma-Like Protein p130, Transforming Growth Factor beta
Show Abstract · Added August 13, 2010
Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1-Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMTV) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV-cyclin D1-Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-D1K2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor beta (TGFbeta), but are relatively resistant to TGFbeta antiproliferative effects. Fibroblasts derived from MMTV-D1K2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70(s6k) and Akt on activating sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGFbeta and HGF, resulting in desmoplasia. The MMTV-D1K2 mice should provide a useful model system for the development of therapeutic approaches to block the stromal desmoplastic reaction that likely plays an important role in the progression of multiple types of human tumors.
1 Communities
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19 MeSH Terms
Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis.
Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR, Muller WJ, Moses HL
(2005) Cancer Res 65: 2296-302
MeSH Terms: Animals, Antigens, Polyomavirus Transforming, Cell Growth Processes, Cell Transformation, Neoplastic, Epithelial Cells, Female, Hyperplasia, Lung Neoplasms, Male, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mammary Tumor Virus, Mouse, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein-Serine-Threonine Kinases, Pulmonary Alveoli, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Transgenes
Show Abstract · Added February 17, 2014
Transforming growth factor-beta (TGF-beta) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-beta signaling in mammary tumorigenesis is complex, as TGF-beta has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-beta signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-beta receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2MGKO). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-beta signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-beta signaling in the carcinoma cells.
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20 MeSH Terms