{"database":"Cell Collective","file_versions":[],"scores":null,"additional":{"omics_type":["Models"],"submitter":["Tomas Helikar"],"version_name":[""],"full_dataset_link":["https://cellcollective.org/#1607/mammalian-cell-cycle"],"model_score":["51.3724"],"default_version":["1"],"ModelFormat":["SBML"],"submitter_affiliation":[""],"submitter_email":[""],"version_id":["1"],"repository":["Cell Collective"],"version_url":["https://cellcollective.org/#1607:1/mammalian-cell-cycle"],"version_description":[""],"pubmed_abstract":["<h4>Background</h4>In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer.<h4>Results</h4>First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation.<h4>Conclusion</h4>In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells."],"pubmed_title":["Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance."],"pubmed_authors":["Sahin Ozgür O, Fröhlich Holger H, Löbke Christian C, Korf Ulrike U, Burmester Sara S, Majety Meher M, Mattern Jens J, Schupp Ingo I, Chaouiya Claudine C, Thieffry Denis D, Poustka Annemarie A, Wiemann Stefan S, Beissbarth Tim T, Arlt Dorit D"],"description_synonyms":["Erbb-2, para Tyrosine, Urogastrone Receptor, Elp-B1, der, Elp-1, Receptors, Errb1, MYC, Myc, Tumor, Epidermal Growth Factor Receptor Family Protein, PIG61, dmTAF[[II]]230, ErbB-1, Kiaa3023, EG:BACN5I9.1, epidermal growth factor-activated receptor activity, Line, cancer of the breast, Kinase, myc, BC, Cell Division Cycles, treatment, TFIID TAF250, cel, Moods, dm/dMyc, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Y, Epidermal Growth Factor Receptor, EGFR family signaling pathway, Epidermal Growth Factor Receptor Kinase, SURGICAL AND MEDICAL PROCEDURES, flb, allergic reaction, cancer of breast, scientific observation, TGF-alpha, 9030024J15Rik, ATP Phosphotransferases, Breast Malignant Neoplasms, single organism signaling, Tumors, dTAF[[II]]230, Elp, dmyc1, EGF Receptors, DEgfr, Monoclonal Antibody, Herceptin, TAF200, integral to membrane, MLN19, para-Tyrosine, Procedure, antibodies, torpedo/egfr, DmIKKgamma, Dm, Monoclonal Antibodies, dIKK, mMyc, Urogastrone, activation, c-neu, Carcinomas, egfr, HD-33, El, Engineerings, DER/EGFR, EGFR, EGfr, EgfR, erbB 1 Proto Oncogene Protein, IKK-gamma, TGF-alpha Receptor, DER flb, erbB-1 Proto-Oncogene Protein, \"mammary neoplasm\" RELATED [], Torpedo/Egfr, D-Myc, ErbB-1 Receptor, L isomer, experimental procedures, Degfr, Transforming-Growth Factor alpha, B cell receptor accessory molecule complex, breast cancer, antagonists and inhibitors, Taf250, DEGFR, Breast Tumors, B lymphocyte receptor complex, l(2)05351, Breast Malignant Tumors, L-Tyrosine, dMyc1, cancer, TAF230, CG10798, D-Egf, dm/myc, Family Receptors, Neoplasms, Transforming Growth Factor alpha Receptor, Mammary Cancers, mENA, protein-containing complex, EK2-6, Transcription Factor, dMyc, dMYC, dIKK-gamma, c-erbB-1 Protein, c erbB 1 Protein, Human, Breast Malignant Tumor, Breast Tumor, sensitive, DmIKK-gamma, EGFr, Egfr, Gene Products, torpedo/Egfr, breast tumor, Cell., TOP, bHLHe57, HER-2/neu, erbB-1, Cycles, Transcription, dTAF[[II]]250, interventionDescription, Mammary Neoplasm, cell, Mammary Carcinoma, Cell Division Cycle, cell-division cycle, Dmyc, DMYc, top, dTAF250, RNCMYC, Malignant Tumor of Breast, Epidermal Growth Factor Urogastrone, Tyrosin, Receptor Tyrosine-protein Kinase erbB-1, bHLHe39, dmyc, Cancer, Neu, NEU, Elp-B1RB1, inhibitors, measuring, Breast Carcinoma, Human Mammary Neoplasm, EGF Receptor, Breast Carcinomas, Epidermal Growth Factor Receptor Family Proteins, TGF-alpha receptor activity, ErbB, ERBB, dEGFR1, Affects, HER-2|neu, Proteins, Proto-Oncogene Protein, BG:DS00004.13, Factor, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Cell, dTAF230, IKKgamma, native protein, tirosina, Neoplasm, TAF[[II]]250/230, Human Mammary Carcinoma, NGL, background, DER/top, Intervention, Taf[[II]]250, c-erbB2, Dmikkgamma, Cancers, wa-2, CG16910, beta, Gene Proteins, Trastuzumab-qyyp, signalling process, Erbb, Epidermal Growth Factor, HER Family, Cancer of Breast, Receptor, breast, DER/faint little ball, malignant tumor of the breast, insensitive, mammary neoplasm, Human Mammary Neoplasms, DmelCG10798, B-cell receptor complex, protein, CD340, c-Myc, c-MYC, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], AI552599, TGF alpha, protein aggregate, d-egf-r, IKKg, KEY, Key, Mammary Neoplasms, malignant neoplasm of breast, c-myc, Trastuzumab beta, membrane bound, ErbB 1, membrane region, Human Mammary Carcinomas, reaction, Proto oncogene c ErbB 1 Protein, Tyr, Cell Cycles, disease management, Therapies, ErbB Receptor, D-EGFR, mammary cancer, B-lymphocyte receptor complex, ATP, NISBD2, DER1, Therapy, Carcinoma, \"breast neoplasm\" EXACT [MTH:120], Wa5, l(2)09261, HER Family Receptors, 2-Amino-3-(p-hydroxyphenyl)propionic acid, Trazimera, TAFII-250, TAF250/230, results, CG10079, Division Cycles, Tyrosine, TAFII250, wa2, Kenny, NOS, Malignant Neoplasm of Breast, Lines, l(1)G0354, Transphosphorylases, Factors, resistant, Division Cycle, l(1)G0359, dEgfr, L-isomer, d-myc, CG17603, TAF[[II]], Treatments, MLN 19, immunoglobulin, Receptor Tyrosine protein Kinase erbB 1, DmelCG16910, Patient, SR3-5, l(2)57DEFa, TKR1, dEGFR, HER, DmHD-33, MRTL, c-ErbB-1 Protein, primary breast cancer, d230, Logics, experimental, C-erb, l(1)G0139, Transforming Growth Factor alpha, mor1, Gene, dTAFII250, EfW1, Intervention or Procedure, antibody, Antibody, anon-WO03040301.171, BCR complex, MYCC, dmTAF1, Taf230, integral component of membrane, resistance, Cycle, c-erbB, \"mammary tumor\" EXACT [CSP2005:2016-0671], EGF receptor activity, Mood, Egf-r, dmIKKgamma, IKK[[gamma]], immunoglobulin complex, Phosphotransferase, sensitivity, TAF250, study, EGF-R, Taf200, Human Mammary, methods, HER-2, experimental section, inhibiteur, Interventional, Torpedo/DER, Taf1p, Cell Division, Transphosphorylase, Cancer of the Breast, top/flb, Family Receptor, Epidermal Growth Factor-Urogastrone, inhibidor, IKK, L Tyrosine, l(2)57EFa, Mammary, Mammary Cancer, Clients, region of membrane, l(2)57Ea, Breast, TAF, mammary tumor, Proto-oncogene, Intervention Strategies, TAF[[II]]250, Epidermal Growth Factor Receptor Protein Tyrosine Kinase, protein complex, Trastuzumab qyyp, mKIAA3023, Cell Lines, inhibitor, l(3)84Ab, Monoclonal, Client, Phosphotransferases, Breast Malignant Neoplasm, epidermal growth factor receptor activity, DmelCG10079, Mammary Carcinomas, p230, Protein, Epidermal Growth Factor Receptor Protein-Tyrosine Kinase, whole membrane, TFIID, Proto-oncogene c-ErbB-1 Protein, HER Family Receptor, Trastuzumab, opsonin activity, antagonists, Breast Neoplasm, transmembrane, TAF[[II]]230, top/DER, Kinases, ERBB1, TAF[II]250, introduction, Protein Gene Products, Egf, EGF, EFG-R, DmelCG17603, Therapeutic, Errp, Breast Cancer, B cell receptor activity, Der, DER, Treatment, transforming growth factor-alpha receptor activity, HER2, DER/torpedo, HER1, TAF1"],"pubmed_title_synonyms":["PIG61, reaction, Trastuzumab-qyyp, Trastuzumab beta, resistance., wa2, Wa5, Errp, Erbb, ERBB, AI552599, Trastuzumab qyyp, Herceptin, 9030024J15Rik, Errb1, ERBB1, wa-2, mENA, Trazimera, HER1, NISBD2, beta, Trastuzumab"],"name_synonyms":["Cell Division Cycles, Cell Division Cycle, Cycles, cell-division cycle, Cell Division, Cell Cycles., Division Cycle, Cell, Cycle, Division Cycles"],"pubmed_abstract_synonyms":["Erbb-2, para Tyrosine, Urogastrone Receptor, Elp-B1, der, Elp-1, Receptors, Errb1, MYC, Myc, Tumor, Epidermal Growth Factor Receptor Family Protein, PIG61, dmTAF[[II]]230, ErbB-1, Kiaa3023, EG:BACN5I9.1, epidermal growth factor-activated receptor activity, Line, cancer of the breast, Kinase, myc, BC, Cell Division Cycles, treatment, TFIID TAF250, cel, Moods, dm/dMyc, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Y, Epidermal Growth Factor Receptor, EGFR family signaling pathway, Epidermal Growth Factor Receptor Kinase, SURGICAL AND MEDICAL PROCEDURES, flb, allergic reaction, cancer of breast, scientific observation, TGF-alpha, 9030024J15Rik, ATP Phosphotransferases, Breast Malignant Neoplasms, single organism signaling, Tumors, dTAF[[II]]230, Elp, dmyc1, EGF Receptors, DEgfr, Monoclonal Antibody, Herceptin, TAF200, integral to membrane, MLN19, para-Tyrosine, Procedure, antibodies, torpedo/egfr, DmIKKgamma, Dm, Monoclonal Antibodies, dIKK, mMyc, Urogastrone, activation, c-neu, Carcinomas, egfr, HD-33, El, Engineerings, DER/EGFR, EGFR, EGfr, EgfR, erbB 1 Proto Oncogene Protein, IKK-gamma, TGF-alpha Receptor, DER flb, erbB-1 Proto-Oncogene Protein, \"mammary neoplasm\" RELATED [], Torpedo/Egfr, D-Myc, ErbB-1 Receptor, L isomer, experimental procedures, Degfr, Transforming-Growth Factor alpha, B cell receptor accessory molecule complex, breast cancer, antagonists and inhibitors, Taf250, DEGFR, Breast Tumors, B lymphocyte receptor complex, l(2)05351, Breast Malignant Tumors, L-Tyrosine, dMyc1, cancer, TAF230, CG10798, D-Egf, dm/myc, Family Receptors, Neoplasms, Transforming Growth Factor alpha Receptor, Mammary Cancers, mENA, protein-containing complex, EK2-6, Transcription Factor, dMyc, dMYC, dIKK-gamma, c-erbB-1 Protein, c erbB 1 Protein, Human, Breast Malignant Tumor, Breast Tumor, sensitive, DmIKK-gamma, EGFr, Egfr, Gene Products, torpedo/Egfr, breast tumor, Cell., TOP, bHLHe57, HER-2/neu, erbB-1, Cycles, Transcription, dTAF[[II]]250, interventionDescription, Mammary Neoplasm, cell, Mammary Carcinoma, Cell Division Cycle, cell-division cycle, Dmyc, DMYc, top, dTAF250, RNCMYC, Malignant Tumor of Breast, Epidermal Growth Factor Urogastrone, Tyrosin, Receptor Tyrosine-protein Kinase erbB-1, bHLHe39, dmyc, Cancer, Neu, NEU, Elp-B1RB1, inhibitors, measuring, Breast Carcinoma, Human Mammary Neoplasm, EGF Receptor, Breast Carcinomas, Epidermal Growth Factor Receptor Family Proteins, TGF-alpha receptor activity, ErbB, ERBB, dEGFR1, Affects, HER-2|neu, Proteins, Proto-Oncogene Protein, BG:DS00004.13, Factor, \"breast tumor\" EXACT [NCI2004_11_17:C2910], Cell, dTAF230, IKKgamma, native protein, tirosina, Neoplasm, TAF[[II]]250/230, Human Mammary Carcinoma, NGL, background, DER/top, Intervention, Taf[[II]]250, c-erbB2, Dmikkgamma, Cancers, wa-2, CG16910, beta, Gene Proteins, Trastuzumab-qyyp, signalling process, Erbb, Epidermal Growth Factor, HER Family, Cancer of Breast, Receptor, breast, DER/faint little ball, malignant tumor of the breast, insensitive, mammary neoplasm, Human Mammary Neoplasms, DmelCG10798, B-cell receptor complex, protein, CD340, c-Myc, c-MYC, \"neoplasm of breast (disorder)\" EXACT [SNOMEDCT_2005_07_31:126926005], AI552599, TGF alpha, protein aggregate, d-egf-r, IKKg, KEY, Key, Mammary Neoplasms, malignant neoplasm of breast, c-myc, Trastuzumab beta, membrane bound, ErbB 1, membrane region, Human Mammary Carcinomas, reaction, Proto oncogene c ErbB 1 Protein, Tyr, Cell Cycles, disease management, Therapies, ErbB Receptor, D-EGFR, mammary cancer, B-lymphocyte receptor complex, ATP, NISBD2, DER1, Therapy, Carcinoma, \"breast neoplasm\" EXACT [MTH:120], Wa5, l(2)09261, HER Family Receptors, 2-Amino-3-(p-hydroxyphenyl)propionic acid, Trazimera, TAFII-250, TAF250/230, results, CG10079, Division Cycles, Tyrosine, TAFII250, wa2, Kenny, NOS, Malignant Neoplasm of Breast, Lines, l(1)G0354, Transphosphorylases, Factors, resistant, Division Cycle, l(1)G0359, dEgfr, L-isomer, d-myc, CG17603, TAF[[II]], Treatments, MLN 19, immunoglobulin, Receptor Tyrosine protein Kinase erbB 1, DmelCG16910, Patient, SR3-5, l(2)57DEFa, TKR1, dEGFR, HER, DmHD-33, MRTL, c-ErbB-1 Protein, primary breast cancer, d230, Logics, experimental, C-erb, l(1)G0139, Transforming Growth Factor alpha, mor1, Gene, dTAFII250, EfW1, Intervention or Procedure, antibody, Antibody, anon-WO03040301.171, BCR complex, MYCC, dmTAF1, Taf230, integral component of membrane, resistance, Cycle, c-erbB, \"mammary tumor\" EXACT [CSP2005:2016-0671], EGF receptor activity, Mood, Egf-r, dmIKKgamma, IKK[[gamma]], immunoglobulin complex, Phosphotransferase, sensitivity, TAF250, study, EGF-R, Taf200, Human Mammary, methods, HER-2, experimental section, inhibiteur, Interventional, Torpedo/DER, Taf1p, Cell Division, Transphosphorylase, Cancer of the Breast, top/flb, Family Receptor, Epidermal Growth Factor-Urogastrone, inhibidor, IKK, L Tyrosine, l(2)57EFa, Mammary, Mammary Cancer, Clients, region of membrane, l(2)57Ea, Breast, TAF, mammary tumor, Proto-oncogene, Intervention Strategies, TAF[[II]]250, Epidermal Growth Factor Receptor Protein Tyrosine Kinase, protein complex, Trastuzumab qyyp, mKIAA3023, Cell Lines, inhibitor, l(3)84Ab, Monoclonal, Client, Phosphotransferases, Breast Malignant Neoplasm, epidermal growth factor receptor activity, DmelCG10079, Mammary Carcinomas, p230, Protein, Epidermal Growth Factor Receptor Protein-Tyrosine Kinase, whole membrane, TFIID, Proto-oncogene c-ErbB-1 Protein, HER Family Receptor, Trastuzumab, opsonin activity, antagonists, Breast Neoplasm, transmembrane, TAF[[II]]230, top/DER, Kinases, ERBB1, TAF[II]250, introduction, Protein Gene Products, Egf, EGF, EFG-R, DmelCG17603, Therapeutic, Errp, Breast Cancer, B cell receptor activity, Der, DER, Treatment, transforming growth factor-alpha receptor activity, HER2, DER/torpedo, HER1, TAF1"],"additional_accession":[]},"is_claimable":false,"name":"Mammalian Cell Cycle","description":"BACKGROUND: In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer. RESULTS: First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation. CONCLUSION: In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells.","dates":{"created":"2011-10-19","publication":"","submission":"2018-06-07","last_modified":"2018-06-07"},"accession":"1607","cross_references":{"pubmed":["19118495"]}}