Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation
Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered net...
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| Veröffentlicht in: | Oncogene 2016-03, Vol.35 (13), p.1643-1656 |
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| creator | Zhang, Y-W Nasto, R E Varghese, R Jablonski, S A Serebriiskii, I G Surana, R Calvert, V S Bebu, I Murray, J Jin, L Johnson, M Riggins, R Ressom, H Petricoin, E Clarke, R Golemis, E A Weiner, L M |
| description | Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene
TOB1
as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of
TOB1
selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers. |
| doi_str_mv | 10.1038/onc.2015.226 |
| format | Article |
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TOB1
as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of
TOB1
selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2015.226</identifier><identifier>PMID: 26165839</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 13/31 ; 13/89 ; 38/79 ; 631/154/51/2053 ; 631/337/505 ; 631/67/1347 ; 631/80/304 ; 82/29 ; 96/2 ; AKT protein ; Analysis ; Apoptosis ; Aromatase ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Care and treatment ; Cell Biology ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Cell survival ; Cell Survival - drug effects ; Cell Survival - genetics ; Development and progression ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Estrogen ; Estrogen receptors ; Estrogens ; Estrogens - pharmacology ; Female ; G1 phase ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Genetic translation ; Health aspects ; HEK293 Cells ; Human Genetics ; Humans ; Innovations ; Internal Medicine ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; MCF-7 Cells ; Medicine ; Medicine & Public Health ; Molecular targeted therapy ; mRNA ; Oncology ; original-article ; Protein arrays ; Receptors ; Signal transduction ; Signal Transduction - drug effects ; Signal Transduction - genetics ; TOR protein ; Tumor cell lines ; Tumor suppressor genes ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumors</subject><ispartof>Oncogene, 2016-03, Vol.35 (13), p.1643-1656</ispartof><rights>Macmillan Publishers Limited 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 31, 2016</rights><rights>Macmillan Publishers Limited 2016.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c567t-5d7474cdff7c4592ed5534847719df6622521cde52842cb1515fc16fa0f4f22d3</citedby><cites>FETCH-LOGICAL-c567t-5d7474cdff7c4592ed5534847719df6622521cde52842cb1515fc16fa0f4f22d3</cites><orcidid>0000-0002-9278-0854 ; 0000-0002-1555-4431</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2015.226$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2015.226$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26165839$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Y-W</creatorcontrib><creatorcontrib>Nasto, R E</creatorcontrib><creatorcontrib>Varghese, R</creatorcontrib><creatorcontrib>Jablonski, S A</creatorcontrib><creatorcontrib>Serebriiskii, I G</creatorcontrib><creatorcontrib>Surana, R</creatorcontrib><creatorcontrib>Calvert, V S</creatorcontrib><creatorcontrib>Bebu, I</creatorcontrib><creatorcontrib>Murray, J</creatorcontrib><creatorcontrib>Jin, L</creatorcontrib><creatorcontrib>Johnson, M</creatorcontrib><creatorcontrib>Riggins, R</creatorcontrib><creatorcontrib>Ressom, H</creatorcontrib><creatorcontrib>Petricoin, E</creatorcontrib><creatorcontrib>Clarke, R</creatorcontrib><creatorcontrib>Golemis, E A</creatorcontrib><creatorcontrib>Weiner, L M</creatorcontrib><title>Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene
TOB1
as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of
TOB1
selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.</description><subject>13/109</subject><subject>13/31</subject><subject>13/89</subject><subject>38/79</subject><subject>631/154/51/2053</subject><subject>631/337/505</subject><subject>631/67/1347</subject><subject>631/80/304</subject><subject>82/29</subject><subject>96/2</subject><subject>AKT protein</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Aromatase</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Cell survival</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - genetics</subject><subject>Development and progression</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Estrogen</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Estrogens - pharmacology</subject><subject>Female</subject><subject>G1 phase</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetic aspects</subject><subject>Genetic translation</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Innovations</subject><subject>Internal Medicine</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>MCF-7 Cells</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Molecular targeted therapy</subject><subject>mRNA</subject><subject>Oncology</subject><subject>original-article</subject><subject>Protein arrays</subject><subject>Receptors</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>TOR protein</subject><subject>Tumor cell lines</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNks1rFTEUxQdR7LO6cy0Dblx0nrmZfMxshGepH1Dopq5DXuZmmjKTTJOZgv-9GV4tTxF1kxDuL-dyDqcoXgPZAqmb98GbLSXAt5SKJ8UGmBQV5y17WmxIy0nV0pqeFC9SuiWEyJbQ58UJFSB4U7ebYtqZu8UlN7vgy2BLTHMMPfrS-Q4nzIc3uD4Wg6m8vvoIVcRBz9iVI5ob7V0aU5mWaQpxdr4v9xF1mkuj879YGhyGcophcBajXpe8LJ5ZPSR89XCfFt8-XVyff6kurz5_Pd9dVoYLOVe8k0wy01krDeMtxY7zmjVMSmg7KwSlnILpkNOGUbMHDtwaEFYTyyylXX1afDjoTst-xM6gn6Me1BTdqON3FbRTv068u1F9uFdMAgXKssC7B4EY7pacixpdWv1oj2FJCmRDeC1A8v9ApWwbWpMVffsbehuW6HMSigoGnDctwN-oVQtaKcWRVq8HVM7bkI2YdbXaCSYpl-wfFMux1cD46vbsQJkYUopoH5MCotaeqdwztfZM5Z5l_M1xuo_wz2JloDoAKY98j_HIwZ8EfwCwxduL</recordid><startdate>20160331</startdate><enddate>20160331</enddate><creator>Zhang, Y-W</creator><creator>Nasto, R E</creator><creator>Varghese, R</creator><creator>Jablonski, S A</creator><creator>Serebriiskii, I G</creator><creator>Surana, R</creator><creator>Calvert, V S</creator><creator>Bebu, I</creator><creator>Murray, J</creator><creator>Jin, L</creator><creator>Johnson, M</creator><creator>Riggins, R</creator><creator>Ressom, H</creator><creator>Petricoin, E</creator><creator>Clarke, R</creator><creator>Golemis, E A</creator><creator>Weiner, L M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9278-0854</orcidid><orcidid>https://orcid.org/0000-0002-1555-4431</orcidid></search><sort><creationdate>20160331</creationdate><title>Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation</title><author>Zhang, Y-W ; Nasto, R E ; Varghese, R ; Jablonski, S A ; Serebriiskii, I G ; Surana, R ; Calvert, V S ; Bebu, I ; Murray, J ; Jin, L ; Johnson, M ; Riggins, R ; Ressom, H ; Petricoin, E ; Clarke, R ; Golemis, E A ; Weiner, L M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c567t-5d7474cdff7c4592ed5534847719df6622521cde52842cb1515fc16fa0f4f22d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13/109</topic><topic>13/31</topic><topic>13/89</topic><topic>38/79</topic><topic>631/154/51/2053</topic><topic>631/337/505</topic><topic>631/67/1347</topic><topic>631/80/304</topic><topic>82/29</topic><topic>96/2</topic><topic>AKT protein</topic><topic>Analysis</topic><topic>Apoptosis</topic><topic>Aromatase</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Y-W</au><au>Nasto, R E</au><au>Varghese, R</au><au>Jablonski, S A</au><au>Serebriiskii, I G</au><au>Surana, R</au><au>Calvert, V S</au><au>Bebu, I</au><au>Murray, J</au><au>Jin, L</au><au>Johnson, M</au><au>Riggins, R</au><au>Ressom, H</au><au>Petricoin, E</au><au>Clarke, R</au><au>Golemis, E A</au><au>Weiner, L M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2016-03-31</date><risdate>2016</risdate><volume>35</volume><issue>13</issue><spage>1643</spage><epage>1656</epage><pages>1643-1656</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene
TOB1
as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of
TOB1
selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26165839</pmid><doi>10.1038/onc.2015.226</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-9278-0854</orcidid><orcidid>https://orcid.org/0000-0002-1555-4431</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2016-03, Vol.35 (13), p.1643-1656 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4712124 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 13/109 13/31 13/89 38/79 631/154/51/2053 631/337/505 631/67/1347 631/80/304 82/29 96/2 AKT protein Analysis Apoptosis Aromatase Breast cancer Breast Neoplasms - genetics Breast Neoplasms - pathology Care and treatment Cell Biology Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell Proliferation - genetics Cell survival Cell Survival - drug effects Cell Survival - genetics Development and progression Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Estrogen Estrogen receptors Estrogens Estrogens - pharmacology Female G1 phase Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Genetic translation Health aspects HEK293 Cells Human Genetics Humans Innovations Internal Medicine Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism MCF-7 Cells Medicine Medicine & Public Health Molecular targeted therapy mRNA Oncology original-article Protein arrays Receptors Signal transduction Signal Transduction - drug effects Signal Transduction - genetics TOR protein Tumor cell lines Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors |
| title | Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T04%3A21%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Acquisition%20of%20estrogen%20independence%20induces%20TOB1-related%20mechanisms%20supporting%20breast%20cancer%20cell%20proliferation&rft.jtitle=Oncogene&rft.au=Zhang,%20Y-W&rft.date=2016-03-31&rft.volume=35&rft.issue=13&rft.spage=1643&rft.epage=1656&rft.pages=1643-1656&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2015.226&rft_dat=%3Cgale_pubme%3EA451531454%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1777197765&rft_id=info:pmid/26165839&rft_galeid=A451531454&rfr_iscdi=true |