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The phosphorylated membrane estrogen receptor and cytoplasmic signaling and apoptosis proteins in human breast cancer
Author(s) -
Mintz Paul J.,
Habib Nagy A.,
Jones Louise J.,
Giamas Georgios,
Lewis Jacqueline S.,
Bowen Rebecca L.,
Coombes R. Charles,
Stebbing Justin
Publication year - 2008
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.23699
Subject(s) - breast cancer , estrogen receptor , cancer research , phosphorylation , medicine , cancer , protein kinase b , western blot , apoptosis , signal transduction , pathology , biology , microbiology and biotechnology , biochemistry , gene
BACKGROUND. Estrogens play a central role in breast cancer development, and the estrogen receptor‒α (ERα) remains the single most important predictor of breast cancer prognosis. Therefore, it is crucial to elucidate pathways that may contribute to ER signaling in clinical specimens. METHODS. Using extracts of fresh invasive ERα‐positive invasive breast carcinomas, ductal carcinoma in situ, and normal glandular breast tissue, the authors performed Western blot analyses of the membrane‐bound ER, 1 of its phosphorylated isoforms, and cytosolic fractions from the same specimens, examining associated proteins (Akt/mitogen‐activated protein kinase pathways). Western blot analysis and immunocapture for the apoptosis and survival factors Bcl‐2 agonist of death (BAD)/Bcl‐2 and BAD/Bcl‐xL were also performed. RESULTS. To the authors' knowledge, this is the first study to report that ERα was phosphorylated in the plasma membrane fractions derived from patients' invasive breast carcinomas. This was associated with a predominance of phosphorylated BAD and a relative reduction in Bcl‐2 compared with both normal tissue and ductal carcinoma in situ, although such studies in fresh tissue did not corroborate these findings. The authors also demonstrated that the BAD/Bcl‐2 and BAD/Bcl‐xL complexes characterized the invasive carcinoma state. CONCLUSIONS. A phosphorylated form of the membrane ER was found to characterize the invasive cancer state. This was associated with a reduction in BAD/Bcl‐2 and BAD/Bcl‐xl. These data implicate the membrane ERα as the in vivo receptor responsible for transcription‐independent cellular responses to estrogens. Cancer 2008. © 2008 American Cancer Society.