Project description:To identify genes that may facilitate early steps of ErbB2/Neu-mediated mammary tumorigenesis, we performed comparative microarray analysis of 5- and 10-week bitransgenic mammary glands (LHxMMTV-neu) in triplicate. Keywords: transgenic mouse, erbB2, MMTV-neu, HER2, mammary tumor, breast cancer
Project description:Transcriptional expression of a restricted set of cancer signal transduction-related gesen were comparatively quantified in HER2/neu transgenic mammary tumors, mesenchymal and epithelial tumor cell lineages, both estabilished from HER-2/neu transgenic tumors, and syngeneic mesenchymal stem cells.
Project description:Transcriptional expression of a restricted set of cancer signal transduction-related gesen were comparatively quantified in HER2/neu transgenic mammary tumors, mesenchymal and epithelial tumor cell lineages, both estabilished from HER-2/neu transgenic tumors, and syngeneic mesenchymal stem cells. In the study presented here, HER-2/neu transgenic mouse mammary tumors, previously described (Galie et al Carcinogenesis 2005 26(11):1868) mesenchymal (A17) and epithelial (BB1) cell lineages estabilished from murine HER-2/neu transgenic mammary tumors, and syngeneic mesenchymal stem cells, underwent transcriptional analysis using microarrays containing probes for 112 signal transduction-related genes and controls (GEArray Q Series Mouse Signal Transduction in Cancer Gene Array, MM-044, Superarray, Friederick, MD, USA).
Project description:CDC25A is a critical target of checkpoint, and its overexpression is observed in various cancers. Here we demonstrate that in vivo levels of Cdc25A expression determine the efficiency of transformation and tumorigenesis. Transgenic expression of CDC25A in murine mammary glands cooperates with tumorigenesis induced by expression of ras or neu. CDC25A- overexpressing tumors display aggressiveness and genomic instability with changes in fragile chromosomal regions, including the region orthologous to human 1p32-36. Experiment Overall Design: Genomic DNA from a MMTV-cdc25a;MMTV-neu double transgenic murine cell line derived from a mammary tumor was compared to normal mammary tissue DNA from the parental strain. A total of two hybridizations were completed.
Project description:Murine models of mammary cancers have proven to be highly informative on numerous fronts including individual gene causation, microenvironmental analyses, and chemoprevention studies. The MMTV-Neu transgenic model of mammary cancer has proven to be a useful model and has been employed in several prevention studies. However, there are certain practical drawbacks to its use including long tumor latencies and a tendency to develop mutations in the transmembrane domain of Neu (unlike human HER2/Neu overexpressing breast cancers). Here we report modifications that were made in an attempt to optimize this mouse model for chemopreventive screening. First, homozygous MMTV-Neu and homozygous P53 KO mice were crossed to create a MMTV-Neu/P53+/- strain (which more closely approximates the genetic make-up of most HER2+ human patients). Second, to overcome the drawback of long tumor latencies, the mice were treated with DMBA for eight weeks. DMBA treatment greatly decreased the latency of mammary carcinomas in the MMTV-Neu mice although the resulting tumors remained histopathologically similar to those from MMTV-Neu control mice. Next, we examined gene expression in tumors derived from MMTV-Neu, MMTV-Neu/p53+/-, and DMBA treated mice. It was found that the characteristic MMTV-Neu tumor-defined expression pattern was still the most prevalent feature of all the MMTV-Neu tumors despite their being crossed to the p53 null allele, treated with DMBA, or both. However, tumors from the DMBA treated animals exhibited many unique gene expression changes including the high expression of stress response, defense, and inflammation genes. Finally, we demonstrated that the RXR agonists UAB30 and Targretin, both inhibited mammary cancer formation in MMTV-Neu mice, including those treated with DMBA. These results demonstrate the potential utility of this murine model for additional chemoprevention studies.
Project description:To identify early events of erbB2-induced mammary tumorigenesis, we compared datasets from 14 genechip experiments including MMTV-neu tumors, preneoplastic neu mammary gland (adjacent neu), and age-matched, wild-type control mammary glands
Project description:CDC25A is a critical target of checkpoint, and its overexpression is observed in various cancers. Here we demonstrate that in vivo levels of Cdc25A expression determine the efficiency of transformation and tumorigenesis. Transgenic expression of CDC25A in murine mammary glands cooperates with tumorigenesis induced by expression of ras or neu. CDC25A- overexpressing tumors display aggressiveness and genomic instability with changes in fragile chromosomal regions, including the region orthologous to human 1p32-36. Experiment Overall Design: Tumors from two mice from each of two conditions (MMTV-cdc25a;MMTV-neu and MMTV-neu) were analyzed in a dye swap experiment. A total of four hybridizations were performed.
Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors.
