Supplementary Table 1a from Global Expression Profiling Identifies Signatures of Tumor Virulence ... more Supplementary Table 1a from Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
Supplementary Table 1c from Global Expression Profiling Identifies Signatures of Tumor Virulence ... more Supplementary Table 1c from Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidenc... more FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidence of pulmonary metastasis. We have demonstrated previously that mammary tumors derived from transgene-positive F1 progeny in particular inbred strains display altered latency, tumor growth rates, and metastatic rates when compared with the FVB/NJ homozygous parent. To identify genes with expression that might be critical in modifying the biological behavior of MMTV-PyMT tumors, we performed a detailed comparative analysis of expression profiles from mammary tumors arising in the parental FVB/NJ background and F1 progeny from crosses with I/LnJ, LP/J, MOLF/Ei, and NZB/B1NJ mice. Compared with normal mammary glands, gene expression profiles of tumors from all five strains exhibited up-regulation of genes involved in cell growth (e.g., Cks1 and CDC25C) and down-regulation of cell adhesion molecules, with many genes associated previously with human breast cancer such as STAT2, CD24 antigen, ...
1551 Defining molecular similarities and differences between genetically engineered mouse models ... more 1551 Defining molecular similarities and differences between genetically engineered mouse models of mammary cancer and human breast cancer is critical to the further understanding of molecular mechanisms of oncogenesis and identifying models most relevant to human disease. One goal of this study was to use expression profiling in an attempt to determine whether several important, oncogenic pathway specific mouse models of mammary cancer could be classified according to the basal - luminal distinctions identified for human breast cancer. We demonstrate that all of the models studied in which p53 is mutated or functionally impaired and a BRCA1 mutant model cluster with human tumors in the basal-type category. All models in which the myc, ras, her2/neu and Polyoma middle T-antigen are driven by the MMTV promoter share molecular characteristics that cluster them with human luminal-type breast tumors. Interestingly, these models have been shown to lack ER-alpha expression (which is stron...
4255 Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assess... more 4255 Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assessing breast cancer prognosis and treatment. Tumors which are ER positive (ER+) may initially respond to Tamoxifen anti-estrogen therapy, but often become hormone-independent. Although Tamoxifen significantly reduces tumor recurrence in certain patients with ER+ breast cancer, over time, approximately 40% of ER+ breast cancers will fail to respond or eventually develop resistance to Tamoxifen, leading to disease progression. Therefore, identification of a gene expression which could predict the response to Tamoxifen treatment would have important clinical application. Additionally, identification of genes involved in Tamoxifen resistance could provide important insights into biologic mechanisms of the non-responsiveness or aquired resistance. Using a cross-species microarray analytic approach, our lab has identified a signature of approximately 300 genes, highly predictive of the ER status...
Page 1. 4 Bioinformatics Approaches to the Analysis of the Transcriptome of Animal Models of Canc... more Page 1. 4 Bioinformatics Approaches to the Analysis of the Transcriptome of Animal Models of Cancer Mark J. Hoenerhoff , Aleksandra M. Michalowski , Ting-Hu Qiu, and Jeffery E. Green ABSTRACT The development of genetically ...
Type 1B astrocytes of the human optic nerve head (ONH) constitutively express neural cell adhesio... more Type 1B astrocytes of the human optic nerve head (ONH) constitutively express neural cell adhesion molecule (NCAM) in vivo and in vitro. Increased synthesis of NCAM has been detected in reactive astrocytes in the glaucomatous ONH of human donor eyes. Several NCAM isoforms are generated through alternate RNA splicing in tissue- and disease-specific patterns. In this study, we analyzed expression
Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Alth... more Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk , the mouse homolog of Frk/rak. We report here that frk / rak −/− mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk / rak −/− epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demons...
Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-k... more Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-knockout to generate mice lacking various combinations of the three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice lacking half of the EGFR ligand family were healthy and fertile, indicative of overlapping or compensatory functions among EGF family members. Nevertheless, pups born to triple null dams frequently died or were runted, suggesting a mammary gland defect. Comparison of individual and combinatorial knockouts established that specific loss of AR severely stunted ductal outgrowth during puberty, consistent with dramatic expression of AR transcripts in normal developing ducts. Surprisingly, loss of all three ligands did not significantly affect cellular proliferation, apoptosis, or ERK activation within terminal end buds. Following pregnancy, most AR single null females, but few triple null females could nurse their young, revealing collaborative roles ...
The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (Py... more The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (Py... more The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
Annals of Physical and Rehabilitation Medicine, 2004
More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14... more More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14 cm-long phosphate fiber laser. The short cavity length shows potential capability for watt level single frequency output.
Annals of Physical and Rehabilitation Medicine, 2004
More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14... more More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14 cm-long phosphate fiber laser. The short cavity length shows potential capability for watt level single frequency output.
The development of breast cancer is thought to occur through a multi-step process. The majority o... more The development of breast cancer is thought to occur through a multi-step process. The majority of breast cancers likely develop over extended periods of time arising from early, pre-invasive lesions such as atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS), progressing to invasive carcinoma and culminating in metastatic disease. However, the molecular mechanisms underlying this process are still poorly understood. The molecular analysis of this multi-step process in human patients is hampered by the difficulty in obtaining tissue samples at all tumor stages, especially from the same patient. In contrast, mouse models of mammary cancer progression are amenable to pathological, genetic and biochemical analyses at all tumor stages. Global gene expression profiling allows for simultaneous interrogation of the expression of thousands of genes and provides important opportunities to identify molecular signatures of tumor progression. This approach provides a means to define ...
The development of breast cancer is thought to occur through a multi-step process. The majority o... more The development of breast cancer is thought to occur through a multi-step process. The majority of breast cancers likely develop over extended periods of time arising from early, pre-invasive lesions such as atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS), progressing to invasive carcinoma and culminating in metastatic disease. However, the molecular mechanisms underlying this process are still poorly understood. The molecular analysis of this multi-step process in human patients is hampered by the difficulty in obtaining tissue samples at all tumor stages, especially from the same patient. In contrast, mouse models of mammary cancer progression are amenable to pathological, genetic and biochemical analyses at all tumor stages. Global gene expression profiling allows for simultaneous interrogation of the expression of thousands of genes and provides important opportunities to identify molecular signatures of tumor progression. This approach provides a means to define ...
Supplementary Table 1a from Global Expression Profiling Identifies Signatures of Tumor Virulence ... more Supplementary Table 1a from Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
Supplementary Table 1c from Global Expression Profiling Identifies Signatures of Tumor Virulence ... more Supplementary Table 1c from Global Expression Profiling Identifies Signatures of Tumor Virulence in MMTV-PyMT-Transgenic Mice
FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidenc... more FVB/N-Tg (MMTV-PyMT)634Mul-transgenic mice develop multifocal mammary tumors with a high incidence of pulmonary metastasis. We have demonstrated previously that mammary tumors derived from transgene-positive F1 progeny in particular inbred strains display altered latency, tumor growth rates, and metastatic rates when compared with the FVB/NJ homozygous parent. To identify genes with expression that might be critical in modifying the biological behavior of MMTV-PyMT tumors, we performed a detailed comparative analysis of expression profiles from mammary tumors arising in the parental FVB/NJ background and F1 progeny from crosses with I/LnJ, LP/J, MOLF/Ei, and NZB/B1NJ mice. Compared with normal mammary glands, gene expression profiles of tumors from all five strains exhibited up-regulation of genes involved in cell growth (e.g., Cks1 and CDC25C) and down-regulation of cell adhesion molecules, with many genes associated previously with human breast cancer such as STAT2, CD24 antigen, ...
1551 Defining molecular similarities and differences between genetically engineered mouse models ... more 1551 Defining molecular similarities and differences between genetically engineered mouse models of mammary cancer and human breast cancer is critical to the further understanding of molecular mechanisms of oncogenesis and identifying models most relevant to human disease. One goal of this study was to use expression profiling in an attempt to determine whether several important, oncogenic pathway specific mouse models of mammary cancer could be classified according to the basal - luminal distinctions identified for human breast cancer. We demonstrate that all of the models studied in which p53 is mutated or functionally impaired and a BRCA1 mutant model cluster with human tumors in the basal-type category. All models in which the myc, ras, her2/neu and Polyoma middle T-antigen are driven by the MMTV promoter share molecular characteristics that cluster them with human luminal-type breast tumors. Interestingly, these models have been shown to lack ER-alpha expression (which is stron...
4255 Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assess... more 4255 Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assessing breast cancer prognosis and treatment. Tumors which are ER positive (ER+) may initially respond to Tamoxifen anti-estrogen therapy, but often become hormone-independent. Although Tamoxifen significantly reduces tumor recurrence in certain patients with ER+ breast cancer, over time, approximately 40% of ER+ breast cancers will fail to respond or eventually develop resistance to Tamoxifen, leading to disease progression. Therefore, identification of a gene expression which could predict the response to Tamoxifen treatment would have important clinical application. Additionally, identification of genes involved in Tamoxifen resistance could provide important insights into biologic mechanisms of the non-responsiveness or aquired resistance. Using a cross-species microarray analytic approach, our lab has identified a signature of approximately 300 genes, highly predictive of the ER status...
Page 1. 4 Bioinformatics Approaches to the Analysis of the Transcriptome of Animal Models of Canc... more Page 1. 4 Bioinformatics Approaches to the Analysis of the Transcriptome of Animal Models of Cancer Mark J. Hoenerhoff , Aleksandra M. Michalowski , Ting-Hu Qiu, and Jeffery E. Green ABSTRACT The development of genetically ...
Type 1B astrocytes of the human optic nerve head (ONH) constitutively express neural cell adhesio... more Type 1B astrocytes of the human optic nerve head (ONH) constitutively express neural cell adhesion molecule (NCAM) in vivo and in vitro. Increased synthesis of NCAM has been detected in reactive astrocytes in the glaucomatous ONH of human donor eyes. Several NCAM isoforms are generated through alternate RNA splicing in tissue- and disease-specific patterns. In this study, we analyzed expression
Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Alth... more Frk/rak belongs to a novel family of Src kinases with epithelial tissue-specific expression. Although developmental expression patterns and functional overexpression in vitro have associated these kinases with growth suppression and differentiation, their physiological functions remain largely unknown. We therefore generated mice carrying a null mutation in iyk , the mouse homolog of Frk/rak. We report here that frk / rak −/− mice are viable, show similar growth rates to wild-type animals, and are fertile. Furthermore, a 2-year study of health and survival did not identify differences in the incidence and spectrum of spontaneous tumors or provide evidence of hyperplasias in frk / rak −/− epithelial tissues. Histological analysis of organs failed to reveal any morphological changes in epithelial tissues that normally express high levels of Frk/rak. Ultrastructural analysis of intestinal enterocytes did not identify defects in brush border morphology or structural polarization, demons...
Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-k... more Targeted mice lacking functional EGF or amphiregulin (AR) were derived and bred to the TGFalpha-knockout to generate mice lacking various combinations of the three ligands. In contrast to EGF receptor (EGFR) knockout mice, triple null mice lacking half of the EGFR ligand family were healthy and fertile, indicative of overlapping or compensatory functions among EGF family members. Nevertheless, pups born to triple null dams frequently died or were runted, suggesting a mammary gland defect. Comparison of individual and combinatorial knockouts established that specific loss of AR severely stunted ductal outgrowth during puberty, consistent with dramatic expression of AR transcripts in normal developing ducts. Surprisingly, loss of all three ligands did not significantly affect cellular proliferation, apoptosis, or ERK activation within terminal end buds. Following pregnancy, most AR single null females, but few triple null females could nurse their young, revealing collaborative roles ...
The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (Py... more The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (Py... more The epistatically interacting modifier loci (Apmt1 and Apmt2) accelerate the polyoma Middle-T (PyVT)-induced mammary tumor. To identify potential candidate genes loci, a combined bioinformatics and genomics strategy was used. On the basis of the assumption that the loci were functioning in the same or intersecting pathways, a search of the literature databases was performed to identify molecular pathways containing genes from both candidate intervals. Among the genes identified by this method were the cell cycle-associated genes Cdc25A and c-Myc, both of which have been implicated in breast cancer. Genomic sequencing revealed noncoding polymorphism in both genes, in the promoter region of Cdc25A, and in the 3' UTR of c-Myc. Molecular and in vitro analysis showed that the polymorphisms were functionally significant. In vivo analysis was performed by generating compound PyVT/Myc double-transgenic animals to mimic the hypothetical model, and was found to recapitulate the age-of-onset phenotype. These data suggest that c-Myc and Cdc25A are Apmt1 and Apmt2, and suggest that, at least in certain instances, bioinformatics can be utilized to bypass congenic construction and subsequent mapping in conventional QTL studies.
Annals of Physical and Rehabilitation Medicine, 2004
More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14... more More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14 cm-long phosphate fiber laser. The short cavity length shows potential capability for watt level single frequency output.
Annals of Physical and Rehabilitation Medicine, 2004
More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14... more More than 3.5 W power at 1535 nm is efficiently generated from a cladding pumped Er:Yb codoped 14 cm-long phosphate fiber laser. The short cavity length shows potential capability for watt level single frequency output.
The development of breast cancer is thought to occur through a multi-step process. The majority o... more The development of breast cancer is thought to occur through a multi-step process. The majority of breast cancers likely develop over extended periods of time arising from early, pre-invasive lesions such as atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS), progressing to invasive carcinoma and culminating in metastatic disease. However, the molecular mechanisms underlying this process are still poorly understood. The molecular analysis of this multi-step process in human patients is hampered by the difficulty in obtaining tissue samples at all tumor stages, especially from the same patient. In contrast, mouse models of mammary cancer progression are amenable to pathological, genetic and biochemical analyses at all tumor stages. Global gene expression profiling allows for simultaneous interrogation of the expression of thousands of genes and provides important opportunities to identify molecular signatures of tumor progression. This approach provides a means to define ...
The development of breast cancer is thought to occur through a multi-step process. The majority o... more The development of breast cancer is thought to occur through a multi-step process. The majority of breast cancers likely develop over extended periods of time arising from early, pre-invasive lesions such as atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS), progressing to invasive carcinoma and culminating in metastatic disease. However, the molecular mechanisms underlying this process are still poorly understood. The molecular analysis of this multi-step process in human patients is hampered by the difficulty in obtaining tissue samples at all tumor stages, especially from the same patient. In contrast, mouse models of mammary cancer progression are amenable to pathological, genetic and biochemical analyses at all tumor stages. Global gene expression profiling allows for simultaneous interrogation of the expression of thousands of genes and provides important opportunities to identify molecular signatures of tumor progression. This approach provides a means to define ...
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