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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2009-1-13
pubmed:abstractText
The oncogene erbB2 is overexpressed in 20% to 30% human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTV-erbB2 mice by more than 11 weeks. By 52 weeks of age, 100% (18 of 18) of the untreated animals had developed mammary tumors, whereas 56% (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10449779, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10502734, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10517669, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10557095, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10754497, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-10866321, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11106684, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11287607, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11420689, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11429595, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11788465, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11874978, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-11986316, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-12400010, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-12438218, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-12559863, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-14517347, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-15126613, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-15378019, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-15514030, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-16273314, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-1648728, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-16678816, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-1751404, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-1751545, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-17637753, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-3523478, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-7748560, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-8083380, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-8108121, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-8290571, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-8455942, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-8597534, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-9069263, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-9154808, http://linkedlifedata.com/resource/pubmed/commentcorrection/19138935-9652737
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1940-6215
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
45-55
pubmed:dateRevised
2010-10-1
pubmed:meshHeading
pubmed-meshheading:19138935-Algorithms, pubmed-meshheading:19138935-Animals, pubmed-meshheading:19138935-Antineoplastic Agents, pubmed-meshheading:19138935-Breast Neoplasms, pubmed-meshheading:19138935-Doxycycline, pubmed-meshheading:19138935-Drug Delivery Systems, pubmed-meshheading:19138935-Gene Expression Regulation, pubmed-meshheading:19138935-Genes, erbB-2, pubmed-meshheading:19138935-Incidence, pubmed-meshheading:19138935-Mammary Tumor Virus, Mouse, pubmed-meshheading:19138935-Mice, pubmed-meshheading:19138935-Mice, Transgenic, pubmed-meshheading:19138935-Peptide Fragments, pubmed-meshheading:19138935-Proto-Oncogene Proteins c-jun, pubmed-meshheading:19138935-Receptors, Estrogen, pubmed-meshheading:19138935-Transcription Factor AP-1, pubmed-meshheading:19138935-Xenograft Model Antitumor Assays
pubmed:year
2008
pubmed:articleTitle
Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors.
pubmed:affiliation
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
pubmed:publicationType
Journal Article
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