ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways.
BACKGROUND
Recently, a novel variant of ER-alpha, ER-alpha36 was identified and cloned. ER-alpha36 lacks intrinsic transcription activity and mainly mediates nongenomic estrogen signaling. Here, we studied the role of nongenomic estrogen signaling pathways mediated by ER-alpha36 in tamoxifen resistance and agonist action.


METHODS
The cellular localization of ER-alpha36 was examined by immunofluorescence in MCF-7 cells and Hec1A cells. MCF-7 breast cancer cells, MCF-7 cells expressing recombinant ER-alpha36 (MCF-7/ER36), Hec1A endometrial cancer cells and Hec1A cells with siRNA knockdown of ER-alpha36 (Hec1A/RNAiER36) were treated with 17beta-estradial (E2) and tamoxifen (TAM) in the absence and presence of kinase inhibitor U0126 and LY294002. We examined phosphorylation of signaling molecules and the expression of c-Myc by immunoblotting, and tumor cell growth by MTT assay.


CONCLUSIONS
ER variant ER-alpha36 enhances TAM agonist activity through activation of the membrane-initiated signaling pathways in endometrial cancer, and that ER-alpha36 is involved in de novo and acquired TAM resistance in breast cancer.
Lin
Sheng-Li
SL
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences and Graduate School, Chinese Academy of Sciences, Beijing, China.
Yan
Li-Ying
LY
Zhang
Xin-Tian
XT
Yuan
Ju
J
Li
Mo
M
Qiao
Jie
J
Wang
Zhao-Yi
ZY
Sun
Qing-Yuan
QY
D017398:Alternative Splicing; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D002070:Butadienes; D002867:Chromones; D047628:Estrogen Receptor alpha; D004967:Estrogens; D048049:Extracellular Signal-Regulated MAP Kinases; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; C489427:MYC protein, human; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one