Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy
Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER⁺) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the effic...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-07, Vol.115 (31), p.7869-7878 |
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| creator | Xiao, Tengfei Li, Wei Wang, Xiaoqing Xu, Han Yang, Jixin Wu, Qiu Huang, Ying Geradts, Joseph Jiang, Peng Fei, Teng Chi, David Zang, Chongzhi Liao, Qi Rennhack, Jonathan Andrechek, Eran Li, Nanlin Detre, Simone Dowsett, Mitchell Jeselsohn, Rinath M. Liu, Shirley Brown, Myles |
| description | Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER⁺) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER⁺ breast cancer. At low CSK levels, as is the case in patients with ER⁺ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER⁺ tumors. |
| doi_str_mv | 10.1073/pnas.1722617115 |
| format | Article |
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We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER⁺ breast cancer. At low CSK levels, as is the case in patients with ER⁺ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER⁺ tumors.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1722617115</identifier><identifier>PMID: 29987050</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cancer therapies ; Endocrine therapy ; Estrogen receptors ; Estrogens ; Estrogens - pharmacology ; Feedback ; Feedback loops ; Female ; Gene Expression Regulation, Enzymologic - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; GTP-binding protein ; Humans ; INAUGURAL ARTICLE ; Kinases ; MCF-7 Cells ; Negative feedback ; Neoplasm Proteins - biosynthesis ; Neoplasm Proteins - genetics ; p21-Activated Kinases - biosynthesis ; p21-Activated Kinases - genetics ; Proteins ; Receptors, Estrogen - biosynthesis ; Receptors, Estrogen - genetics ; src-Family Kinases - biosynthesis ; src-Family Kinases - genetics ; Therapy ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-07, Vol.115 (31), p.7869-7878</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright © 2018 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Jul 31, 2018</rights><rights>Copyright © 2018 the Author(s). Published by PNAS. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-585a8f1599bd6c434c34f950dacca4c9dc09963a437f052421102cd2e1536c8d3</citedby><cites>FETCH-LOGICAL-c509t-585a8f1599bd6c434c34f950dacca4c9dc09963a437f052421102cd2e1536c8d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26529347$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26529347$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29987050$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xiao, Tengfei</creatorcontrib><creatorcontrib>Li, Wei</creatorcontrib><creatorcontrib>Wang, Xiaoqing</creatorcontrib><creatorcontrib>Xu, Han</creatorcontrib><creatorcontrib>Yang, Jixin</creatorcontrib><creatorcontrib>Wu, Qiu</creatorcontrib><creatorcontrib>Huang, Ying</creatorcontrib><creatorcontrib>Geradts, Joseph</creatorcontrib><creatorcontrib>Jiang, Peng</creatorcontrib><creatorcontrib>Fei, Teng</creatorcontrib><creatorcontrib>Chi, David</creatorcontrib><creatorcontrib>Zang, Chongzhi</creatorcontrib><creatorcontrib>Liao, Qi</creatorcontrib><creatorcontrib>Rennhack, Jonathan</creatorcontrib><creatorcontrib>Andrechek, Eran</creatorcontrib><creatorcontrib>Li, Nanlin</creatorcontrib><creatorcontrib>Detre, Simone</creatorcontrib><creatorcontrib>Dowsett, Mitchell</creatorcontrib><creatorcontrib>Jeselsohn, Rinath M.</creatorcontrib><creatorcontrib>Liu, Shirley</creatorcontrib><creatorcontrib>Brown, Myles</creatorcontrib><title>Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER⁺) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER⁺ breast cancer. At low CSK levels, as is the case in patients with ER⁺ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER⁺ tumors.</description><subject>Biological Sciences</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Endocrine therapy</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Estrogens - pharmacology</subject><subject>Feedback</subject><subject>Feedback loops</subject><subject>Female</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>GTP-binding protein</subject><subject>Humans</subject><subject>INAUGURAL ARTICLE</subject><subject>Kinases</subject><subject>MCF-7 Cells</subject><subject>Negative feedback</subject><subject>Neoplasm Proteins - biosynthesis</subject><subject>Neoplasm Proteins - genetics</subject><subject>p21-Activated Kinases - biosynthesis</subject><subject>p21-Activated Kinases - genetics</subject><subject>Proteins</subject><subject>Receptors, Estrogen - biosynthesis</subject><subject>Receptors, Estrogen - genetics</subject><subject>src-Family Kinases - biosynthesis</subject><subject>src-Family Kinases - genetics</subject><subject>Therapy</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctOGzEUhi1EBYF23VUrS6wHjm_j8aYSQpRWQuoG1pbjOQ6TTsZT20HKjnfgDfsknSgpl9VZnO__z-Un5DODcwZaXIyDy-dMc14zzZg6IDMGhlW1NHBIZgBcV43k8pic5LwEAKMaOCLH3JhGg4IZWV7nkuIChyrhYt27gi0NiO3c-d-0j3GkfbfqSqblASmG0HnnNzQGinsdTehxLDH9fXouLi1w6zBP6HKh3g0e01aa3Lj5SD4E12f8tK-n5P779d3Vj-r2183Pq8vbyiswpVKNck1gyph5W3sppBcyGAWt895Jb1oPxtTCSaEDKC45Y8B9y5EpUfumFafk2853XM9X2HocSnK9HVO3cmljo-vs-87QPdhFfLQ1aD29cjI42xuk-Gc9HWqXcZ2GaWfLGTCjhdFyoi52lE8x54ThZQIDuw3HbsOxr-FMiq9vF3vh_6cxAV92wDJPD33t14obIbX4BxDQmEo</recordid><startdate>20180731</startdate><enddate>20180731</enddate><creator>Xiao, Tengfei</creator><creator>Li, Wei</creator><creator>Wang, Xiaoqing</creator><creator>Xu, Han</creator><creator>Yang, Jixin</creator><creator>Wu, Qiu</creator><creator>Huang, Ying</creator><creator>Geradts, Joseph</creator><creator>Jiang, Peng</creator><creator>Fei, Teng</creator><creator>Chi, David</creator><creator>Zang, Chongzhi</creator><creator>Liao, Qi</creator><creator>Rennhack, Jonathan</creator><creator>Andrechek, Eran</creator><creator>Li, Nanlin</creator><creator>Detre, Simone</creator><creator>Dowsett, Mitchell</creator><creator>Jeselsohn, Rinath M.</creator><creator>Liu, Shirley</creator><creator>Brown, Myles</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20180731</creationdate><title>Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy</title><author>Xiao, Tengfei ; Li, Wei ; Wang, Xiaoqing ; Xu, Han ; Yang, Jixin ; Wu, Qiu ; Huang, Ying ; Geradts, Joseph ; Jiang, Peng ; Fei, Teng ; Chi, David ; Zang, Chongzhi ; Liao, Qi ; Rennhack, Jonathan ; Andrechek, Eran ; Li, Nanlin ; Detre, Simone ; Dowsett, Mitchell ; Jeselsohn, Rinath M. ; Liu, Shirley ; Brown, Myles</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-585a8f1599bd6c434c34f950dacca4c9dc09963a437f052421102cd2e1536c8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Biological Sciences</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - 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We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER⁺ breast cancer. At low CSK levels, as is the case in patients with ER⁺ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER⁺ tumors.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>29987050</pmid><doi>10.1073/pnas.1722617115</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biological Sciences Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cancer therapies Endocrine therapy Estrogen receptors Estrogens Estrogens - pharmacology Feedback Feedback loops Female Gene Expression Regulation, Enzymologic - drug effects Gene Expression Regulation, Neoplastic - drug effects GTP-binding protein Humans INAUGURAL ARTICLE Kinases MCF-7 Cells Negative feedback Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics p21-Activated Kinases - biosynthesis p21-Activated Kinases - genetics Proteins Receptors, Estrogen - biosynthesis Receptors, Estrogen - genetics src-Family Kinases - biosynthesis src-Family Kinases - genetics Therapy Tumors |
| title | Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy |
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