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PMID:20935677

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Citation

Zhang, XT, Kang, LG, Ding, L, Vranic, S, Gatalica, Z and Wang, ZY (2011) A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30:770-80

Abstract

It is prevailingly thought that estrogen signaling is not involved in development of estrogen receptor (ER)-negative breast cancer. However, there is evidence indicating that ovariectomy prevents the development of both ER-positive and -negative breast cancer, suggesting that estrogen signaling is involved in the development of ER-negative breast cancer. Previously, our laboratory cloned a variant of ER-α, ER-α36, and found that ER-α36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-α36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-α36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-α36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-α36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-α36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of epidermal growth factor receptor (EGFR) and Src. EGFR signaling activated ER-α36 transcription through an AP1 site in the ER-α36 promoter, and ER-α36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-α36 mediates nongenomic estrogen signaling through the EGFR/Src/ERK signaling pathway in ER-negative breast cancer cells and suggested that a subset of ER-negative breast tumors that expresses ER-α36, retains responsiveness to mitogenic estrogen signaling.

Links

PubMed PMC3020987 Online version:10.1038/onc.2010.458

Keywords

Animals; Antineoplastic Agents, Hormonal/pharmacology; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Carcinoma/drug therapy; Carcinoma/metabolism; Cell Line, Tumor; Cell Proliferation/drug effects; Chromones/pharmacology; Enzyme Inhibitors/pharmacology; Estrogen Receptor alpha/metabolism; Estrogens/metabolism; Estrogens/pharmacology; Feedback, Physiological; Female; Humans; Mice; Mice, Nude; Morpholines/pharmacology; Ovariectomy; Pyrimidines/metabolism; RNA, Small Interfering/genetics; Receptor, Epidermal Growth Factor/metabolism; Shc Signaling Adaptor Proteins/metabolism; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03372-4

F

Seeded From UniProt

complete

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12931

F

Seeded From UniProt

complete

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29353

F

Seeded From UniProt

complete

HUMAN:SRC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:SRC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12931

F

Seeded From UniProt

complete

HUMAN:SRC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29353

F

Seeded From UniProt

complete

HUMAN:SRC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03372-4

F

Seeded From UniProt

complete

HUMAN:SHC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:SHC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03372-4

F

Seeded From UniProt

complete


See also

References

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Internal error - GONUTS

GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

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Internal error

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[9570b4f71a617e879f850cff] /wiki/index.php/PMID:20935677 Error from line 252 of /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php: Call to a member function getIdentifier() on null

Backtrace:

#0 /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php(70): AnnotationLinks::getQuickGOannotations(string, array)
#1 /var/www/html/go/wiki/includes/parser/Parser.php(3888): AnnotationLinks::renderAnnotations(NULL, array, Parser, PPFrame_DOM)
#2 /var/www/html/go/wiki/includes/parser/Preprocessor_DOM.php(1362): Parser->extensionSubstitution(array, PPFrame_DOM)
#3 /var/www/html/go/wiki/includes/parser/Parser.php(2942): PPFrame_DOM->expand(DOMElement, integer)
#4 /var/www/html/go/wiki/includes/parser/Parser.php(1293): Parser->replaceVariables(string)
#5 /var/www/html/go/wiki/includes/parser/Parser.php(443): Parser->internalParse(string)
#6 /var/www/html/go/wiki/includes/content/WikitextContent.php(323): Parser->parse(string, Title, ParserOptions, boolean, boolean, integer)
#7 /var/www/html/go/wiki/includes/content/AbstractContent.php(516): WikitextContent->fillParserOutput(Title, integer, ParserOptions, boolean, ParserOutput)
#8 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(231): AbstractContent->getParserOutput(Title, integer, ParserOptions, boolean)
#9 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(126): RefreshLinksJob->runForTitle(Title)
#10 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(296): RefreshLinksJob->run()
#11 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(193): JobRunner->executeJob(RefreshLinksJob, Wikimedia\Rdbms\LBFactorySimple, BufferingStatsdDataFactory, integer)
#12 /var/www/html/go/wiki/includes/MediaWiki.php(1002): JobRunner->run(array)
#13 /var/www/html/go/wiki/includes/MediaWiki.php(988): MediaWiki->triggerSyncJobs(integer, MediaWiki\Logger\LegacyLogger)
#14 /var/www/html/go/wiki/includes/MediaWiki.php(912): MediaWiki->triggerJobs()
#15 /var/www/html/go/wiki/includes/MediaWiki.php(727): MediaWiki->restInPeace(string, boolean)
#16 /var/www/html/go/wiki/includes/MediaWiki.php(750): MediaWiki->{closure}()
#17 /var/www/html/go/wiki/includes/MediaWiki.php(557): MediaWiki->doPostOutputShutdown(string)
#18 /var/www/html/go/wiki/index.php(42): MediaWiki->run()
#19 {main}

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