Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2009-6-2
pubmed:abstractText
Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor-alpha (ERalpha)-positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ERalpha in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ERalpha mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective "addiction" to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ERalpha mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy.
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-10068276, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-10614662, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-10945602, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-11029009, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-11507039, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-12525766, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-12775708, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-14633737, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15026626, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15034868, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15569636, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15604293, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15613443, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15713898, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15784165, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15867390, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-15958587, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16000569, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16084234, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16113102, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16280033, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16382068, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16894390, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-16959974, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-17055257, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-17172405, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-17344846, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-17545528, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-1784232, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-18559539, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-1899037, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-2632259, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-7559875, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-7563152, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-8126115, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-8625307, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-9337862, http://linkedlifedata.com/resource/pubmed/commentcorrection/19487288-9528769
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
69
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4724-32
pubmed:dateRevised
2011-3-10
pubmed:meshHeading
More...