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. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2011-10-19T10:49:22Z 2018-06-07T11:22:45Z

<font size="2" face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><em>Epidermal growth factor</em></span></font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P01133</span></font></div><div><font face="Georgia" size="2">Gene Name: EGF</font></div><div><font face="Georgia" size="2">Gene ID: 1950</font></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">v-akt murine thymoma viral oncogene homolog 1 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P31749" style="text-decoration: none; background-color: rgb(255, 255, 255);">P31749</a></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><span class="highlight" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><a href="http://www.ncbi.nlm.nih.gov/gene/207" ref="ordinalpos=1&ncbi_uid=207&link_uid=207" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">AKT1</a></span></font></div><div><font face="Georgia" size="2">NCBI ID: <span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">207</span></font></div></div>

2015-11-15T16:19:29Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB2-receptor: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><span style="font-family: Georgia; font-size: small; line-height: 16px;">Receptor tyrosine-protein kinase erbB-2</span></p><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><div><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 16.78819465637207px; white-space: nowrap;"><br/></span></font></div></div>

2015-11-15T16:19:29Z

<p><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB3-receptor: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P00533</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">1956</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 16.78819465637207px; white-space: nowrap;"><br/></span></font></div>

2015-11-15T16:19:29Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P00533</span></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">1956</span></font></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Cyclin-dependent kinase 4 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P11802" style="text-decoration: none; background-color: rgb(255, 255, 255);">P11802</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1019" ref="ordinalpos=1&ncbi_uid=1019&link_uid=1019" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">CDK4</span></a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI ID: 1019</font></span></div>

2015-11-15T16:19:29Z

<div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);">\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-erb-b2 erythroblastic\r\nleukemia viral oncogene\r\nhomolog 2,\r\nneuro/glioblastoma derived\r\noncogene homolog (avian) </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-2</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div>

2015-11-15T16:19:29Z

<p><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB2-receptor:</font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P00533</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">1956</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-2</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px;"><br/></span></font></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Cyclin </span><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">E1</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P24864" style="text-decoration: none; background-color: rgb(255, 255, 255);">P24864</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/898" ref="ordinalpos=1&ncbi_uid=898&link_uid=898" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">CCNE1</a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 898</font></span></div>

2015-11-15T16:19:29Z

<div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);">\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-erb-b2 erythroblastic\r\nleukemia viral oncogene\r\nhomolog 3 (avian) </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div>

2015-11-15T16:19:29Z

<font face="Georgia"><span class="highlight" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Cyclin</span><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> D1 [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><span class="highlight">Homo </span>sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P24385" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P24385</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/595" ref="ordinalpos=6&ncbi_uid=595&link_uid=595" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">CCND1</a></font></div><div><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia">NCBI Gene ID: 595</font></span></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">cyclin-dependent kinase 6 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q00534" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q00534</a></font></div><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1021" ref="ordinalpos=1&ncbi_uid=1021&link_uid=1021" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">CDK6</span></a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 1021</font></span></div>

2015-11-15T16:19:29Z

<font face="Georgia"><span style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);">Cyclin-dependent kinase 2 [</span><em style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; font-size: 13.333333969116211px; background-color: rgb(255, 255, 255);">(human)]</span></font><div style="line-height: normal;"><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P24941" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P24941</a></font></div><div style="line-height: normal;"><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1017" ref="ordinalpos=1&ncbi_uid=1017&link_uid=1017" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">CDK2</span></a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia">NCBI Gene ID: 1017</font></span></div>

2015-11-15T16:19:29Z

<font face="Arial, Verdana" size="2">cyclin-dependent kinase inhibitor 2B (CDKN2B)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P42772</font></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1A (CDKN1A)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: Q6FI05</font></div></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1B (CDKN1B)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P46527</font></div></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1C (CDKN1C)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P49918</font></div></div>

2015-11-15T16:19:29Z

<font face="Georgia"><span style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase kinase 1 [</span><em style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia"><span style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q02750" style="text-decoration: none; font-size: small; background-color: rgb(255, 255, 255);">Q02750</a></font></div><div><font face="Georgia"><span style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/5604" ref="ordinalpos=12&ncbi_uid=5604&link_uid=5604" style="color: rgb(100, 42, 143); font-size: 13px; line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K1</a></font></div><div><span style="font-size: 13px; line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia">Gene ID:5604</font></span></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Estrogen receptor 1 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><span class="highlight">Homo sapiens</span></em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q9UKM7" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q9UKM7</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2099" ref="ordinalpos=1&ncbi_uid=2099&link_uid=2099" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">ESR1</a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 2099</font></span></div>

2015-11-15T16:19:29Z

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-myc myelocytomatosis viral\r\noncogene homolog</font></p><p><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P01106" style="text-decoration: none; background-color: rgb(255, 255, 255);">P01106</a></font></p><p><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/4609" ref="ordinalpos=2&ncbi_uid=4609&link_uid=4609" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">MYC</a></font></p><p><font face="Georgia" size="2"><font size="2">Gene ID: </font><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">4609</span></font></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Retinoblastoma 1 [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID:  </span><a href="http://www.uniprot.org/uniprot/P06400" style="text-decoration: none; background-color: rgb(255, 255, 255);">P06400</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5925" ref="ordinalpos=1&ncbi_uid=5925&link_uid=5925" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">RB1</a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID:  5925</font></span></div>

This component represents the hyperphosphorylated form of pRB.

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Insulin-like growth factor 1 receptor [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P08069" style="text-decoration: none; background-color: rgb(255, 255, 255);">P08069</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/3480" ref="ordinalpos=1&ncbi_uid=3480&link_uid=3480" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">IGF1R</span></a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 3480</font></span></div>

2015-11-15T16:19:29Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Cyclin-dependent kinase inhibitor 1A (</span><span class="highlight" style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">p21</span><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">, Cip1) [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q9H633" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q9H633</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1026" ref="ordinalpos=1&ncbi_uid=1026&link_uid=1026" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">CDKN1A</a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 1026</font></span></div>

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<font face="Georgia" size="2">ErbB2 and ErbB3 dimers activate the PI3K pathway [1, 4].</font>

<font face="Georgia" size="2">IGF1R activates the protein IRS-1, which in turn activates the PI3K pathway [1,2]. </font>

<font face="Georgia" size="2">ErbB1 and ErbB2 dimers activate the PI3K pathway [1,3]. </font>

* Add any laboratory findings here. You can use bullet points to separate different findings. <br>* Additional findings.

S_2 1 S_19 1 S_8 1 S_5 1 S_4 1

<font face="Georgia">ErbB2_3 is activated by ErbB2 and ErbB3 [1]. </font>

<span style="font-family: Georgia;">ErbB3 is required to form dimers with ErbB2_3 [1,2,3]. </span>

<font face="Georgia">ErbB2 is required to form dimers with ErbB2_3 [1,2,3]. </font>

S_7 1 S_10 1

<font face="Georgia">ErbB1 and ErbB3 are both required to activate ErbB1_3 [1]. </font>

<font face="Georgia">ErbB1 is required to form ErbB1_3 dimers [1, 2, 3]. </font>

<span style="font-family: Georgia;">ErbB3 is required to form ErbB1_3 dimers [1, 2, 3]. </span>

S_5 1 S_10 1

<font face="Georgia">ErbB1 is activated by EGF [1]. </font>

<font face="Georgia">EGf binds and activates ErbB1 [1, 2]. </font>

S_3 1

<font face="Georgia" size="2">CDK4 is activated by CycD1 and inhibited by p21 or p27. Both p21 and p27's negative activity s dominant over CycD1 [1]. </font>

<font face="Georgia" size="2">p21 inhibits the activity of CDK4 [1,3]. </font>

<font face="Georgia">p27 inhibits the activity of CDK4 [1,4]. </font>

<font face="Georgia" size="2">CycD1 bind and activates CDK4 [1,2]. </font>

S_11 1 S_14 1 S_20 1

<span style="font-family: Georgia;">EGF activates ErbB2 [1].</span>

<font face="Georgia">EGF activates ErbB2 [1, 2].</font>

S_3 1

<font face="Georgia">ErbB1 and ErbB2 are both required to activate ErbB1_2 [1]. </font>

<font face="Georgia">ErbB1 is required to form ErbB1_2 [1, 2, 3]. </font>

<span style="font-family: Georgia;">ErbB2 is required to form ErbB1_2 [1, 2, 3]. </span>

S_5 1 S_7 1

<font face="Georgia" size="2">cMYC activates CycE1 [1]. </font>

<font face="Georgia" size="2">MYC activates Cyclin E [1, 2]. </font>

S_17 1

<font face="Georgia">EGF activates ErbB3 [1]. </font>

<font face="Georgia" size="2">EGF activates ErbB3 [1,2]. </font>

S_3 1

<font face="Georgia" size="2">ERa and cMYC are both required for activation of CycD1. In addition, either AKT1 or MEK1 are required to activate CycD1 [1]. </font>

<font face="Georgia" size="2">Sustained ERK activity activates CycD1 [1, 5]. </font>

<font face="Georgia" size="2">ER alpha activates CycD1 [1, 4]. </font>

<font face="Georgia">CycD1 is activated by cMYC [1,2]. </font>

<font face="Georgia" size="2">Akt stabilizes CycD1 [1, 3]. </font>

S_1 1 S_17 1 S_16 1 S_15 1 S_16 1 S_17 1

<font face="Georgia" size="2">CDK6 is activated by CycD1 [1]. </font>

<font face="Georgia" size="2">CycD1 binds to and activates CDK6 [1,2]. </font>

S_11 1

<font face="Georgia" size="2">CDK2 is activated by CycE1. CDK2 is inhibited by both p21 and p27 independently. Each inhibitor is sufficient for the repression of CDK2 activity [1]. </font>

<font face="Georgia" size="2">Cyclin E binds and activates CDK2 [1,4]. </font>

<font face="Georgia" size="2">Reduction of p21 activates the Cyclin E/CDK2 complex [1,2]. </font>

<font face="Georgia" size="2">p27 inhibits CDK2 [1,3]. </font>

S_9 1 S_20 1 S_14 1

<font face="Georgia">ERa activates p27. Akt1, CDK2, CDK4, and cMYC are all inhibitors of p27 and each one is individually sufficient to inhibit ERa's activation of p27 [1]. </font>

<font face="Georgia">ER alpha activates p27 [1,2]. </font>

<font face="Georgia">cMYC inhibits p27 [1,3]. </font>

<font face="Georgia">CDK2 phosphorylates p27 and targets it for degradation [1,5,6]. </font>

<font face="Georgia">CDK4 sequesters p27 and inhibits it [1,4]. </font>

<font face="Georgia" size="2">Akt1 phosphorylates p27 and inhibits p27 [1,7]. </font>

S_16 1 S_13 1 S_6 1 S_1 1 S_17 1

<font face="Georgia">Mek1 can be activated by ErbB1, ErbB1_2, ErbB1_3, ErbB2_3, or IGF1R [1]. </font>

<font face="Georgia" size="2">ErbB1 dimers are effective in activating the Ras/MAPK pathway [1,2]. </font>

<span style="font-family: Georgia; font-size: small;">ErbB2 dimers are effective in activating the Ras/MAPK pathway [1,2]. </span>

<span style="font-family: Georgia; font-size: small;">ErbB1 dimers are effective in activating the Ras/MAPK pathway [1,2]. </span>

<font face="Georgia">IGF1R activates the Ras/MAPK pathway [1,3]. </font>

<span style="font-family: Georgia; font-size: small;">ErbB1 dimers are effective in activating the Ras/MAPK pathway [1,2]. </span>

S_2 1 S_19 1 S_5 1 S_4 1 S_8 1

<font face="Georgia">Akt1 or Mek1 can each individually activate ERa [1]. </font>

<font face="Georgia" size="2">ER activation is mediated by both cAMP and the APT1 site [1, 3].</font>

<font face="Georgia">Akt1 causes ligand independent activation of ER alpha [1, 2]. </font>

S_1 1 S_15 1

<font face="Georgia">AKT1 or ERa or MEK1 can each independently activate cMYC [1].</font>

<font face="Georgia" size="2">cMYC is activated by ER alpha [1, 4]. </font>

<font face="Georgia" size="2">The Ras/Raf/MEK/MAPK pathway activates cMYC [1,2,3</font><span style="font-family: Georgia; font-size: small;">]. </span>

<font face="Georgia" size="2">AKT stimulates the activation of cMYC [1, 3]. </font>

S_1 1 S_16 1 S_15 1

<font face="Georgia">The hyperphosphorylated form of pRB (represented as just pRB in this model) can be activated by the joint activity of CDK4 and CDK6 or alternately by the joint activity of CDK4, CDK6 and CDK2 [1]. </font>

<font face="Georgia">CDK2 also contributes to the phosphorylation of pRB [1,2,3]. </font>

<font face="Georgia">CDK4 phosphorylates pRB at Ser 807/811 [1,4,5]. </font>

<font face="Georgia" size="2">CDK6 phosphorylates pRB [1,5]. </font>

S_13 1 S_6 1 S_12 1 S_6 1 S_12 1

<font face="Georgia" size="2">IGF1R can be activated by Akt1 or ERa. ErbB2_3 is an inhibitor of IGF1R and is dominant over both activators [1]. </font>

<font face="Georgia" size="2">ER alpha increases the expression of IGF1R by inducing phosphorylation [1,3,4]. </font>

<font face="Georgia" size="2">ErbB2_3 decreases expression of IGF1R [1,2]. </font>

<font face="Georgia" size="2">Akt1 increases expression of IGF1R [1,5]. </font>

S_1 1 S_2 1 S_16 1 S_2 1

<font face="Georgia" size="2">p21 is activated by ERa. Akt1, CDK4, and cMYC are all inhibitors of p21 and each are sufficient to suppress the activation of ER1 [1]. </font>

<font face="Georgia" size="2">ER alpha induces the expression of p21 [1,3,4]. </font>

<font face="Georgia">Activated cMYC inhibits p21 [1,3,4]. </font>

<font face="Georgia">CDK4 sequesters and inhibits p21 [1,5]. </font>

<font face="Georgia" size="2">Akt1 phosphorylates p21 and thereby inhibits it [1,2]. </font>

S_16 1 S_6 1 S_1 1 S_17 1