Project description:Purpose: To explore the endogenous expression pattern of Erbb2. Methods: Approximately 1000 hearts dissected from 72 hpf Tg(myl7:mCherry) embryos were digested in 0.25% trypsin-EDTA solution for single-cell RNA sequencing. Results: We found that ventricular Erbb2 expression was highly enriched in subcluster 0 and 2, but weakly expressed in subcluster 3, 10 and 12. Conclusions: Erbb2 exhibits heterogeneous expression during trabeculation.
Project description:Purpose: To investigate the mechanism of how Notch-Erbb2 signaling coordinated the cardiomyocyte interactions to direct ventricular chamber morphogenesis. Methods: Approximately 1000 hearts dissected from 96 hpf Tg(myl7:mCherry) embryos were collected for RNA sequencing. Results: We found that the expression levels of most genes involved in PI3K-AKT signaling and actomyosin structure organization increased prominently. Conclusions: Notch prevents excessive trabeculation by intercepting Erbb2-PI3K signaling pathway.
Project description:The tyrosine kinase ErbB2 positive breast tumors have more aggressive tumor growth, poorer clinical outcome, and more resistance to radiotherapy, chemotherapy and hormone therapy. A humanized anti-ErbB2 monoclonal antibody Herceptin and a small molecules inhibitor Lapatinib were developed and approved by FDA to treat patients with ErbB2 amplification and overexpression. Unfortunately, most ErbB2+ breast cancers do not respond to Herceptin and Lapatinib, and the majority of responders become resistant within 12 months of initial therapy (defined as secondary drug resistance). Such differences in response to Lapatinib treatment is contributed by substantial heterogeneity within ErbB2+ breast cancers. To address this possibility, we carried out transcriptomic analysis of mammary tumors from genetically diverse MMTV-ErbB2 mice. This will help us to have a better understanding of the heterogeneous response to ErbB2 targeted therapy and permit us to design better and more individualized (personalized) treatment strategies for human ErbB2 positive breast cancer. 214 MMTV-ErbB2 mammary tumors and 8 normal mammary glands were analyzed by Affymetrix microarrays.
Project description:The tyrosine kinase ErbB2 positive breast tumors have more aggressive tumor growth, poorer clinical outcome, and more resistance to radiotherapy, chemotherapy and hormone therapy. A humanized anti-ErbB2 monoclonal antibody Herceptin and a small molecules inhibitor Lapatinib were developed and approved by FDA to treat patients with ErbB2 amplification and overexpression. Unfortunately, most ErbB2+ breast cancers do not respond to Herceptin and Lapatinib, and the majority of responders become resistant within 12 months of initial therapy (defined as secondary drug resistance). Such differences in response to Lapatinib treatment is contributed by substantial heterogeneity within ErbB2+ breast cancers. To address this possibility, we carried out transcriptomic analysis of mammary tumors from genetically diverse MMTV-ErbB2 mice. This will help us to have a better understanding of the heterogeneous response to ErbB2 targeted therapy and permit us to design better and more individualized (personalized) treatment strategies for human ErbB2 positive breast cancer.
Project description:15-25% of breast cancers (BC) show ERBB2-amplification and overexpression of the encoded ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs may help understand their behavior and design new therapeutic strategies. In this study, we defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. We first identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, we identified 17 genome regions affected by copy number aberration (CNA). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/ß-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2-amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. We have shown that ERBB2 BCs are heterogeneous and identified genomic features that may be useful in the design of therapeutical strategies
Project description:Background: The targeted ERBB2 therapy, trastuzumab, has had a tremendous impact on management of patients with HER2+ breast cancer, leading to development and increased use of further HER2 targeted therapies. The major clinical side effect is cardiotoxicity but the mechanism is largely unknown. On the basis that gene expression is known to be altered in multiple models of heart failure, we examined differential gene expression of iPSC derived cardiomyocytes treated at day 11 with the ERBB2 targeted monoclonal antibody, trastuzumab for 48 hours and the small molecule tyrosine kinase inhibitor of EGFR and ERBB2. Methods: Transcriptome sequencing was performed on four replicates from each group (48 hours untreated, 48 hours trastuzumab and 48 hours lapatinib) and differential gene expression analyses were performed on each treatment group relative to untreated cardiomyocytes. Results: 517 and 1,358 genes were differentially expressed, p<0.05, respectively in cardiomyocytes treated with trastuzumab and lapatinib. Gene ontology analyses revealed in cardiomyocytes treated with trastuzumab, significant down-regulation of genes involved in small molecule metabolism (p=3.22x10-9) and cholesterol (p=0.01) and sterol (p=0.03) processing. Conclusions: Our study suggests dysregulation of cardiac gene expression and metabolism as key elements of ERBB2 signaling that could potentially be early biomarkers of cardiotoxicity.
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.