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Cancer. 2008 Sep 15;113(6):1489-95. doi: 10.1002/cncr.23699.

The phosphorylated membrane estrogen receptor and cytoplasmic signaling and apoptosis proteins in human breast cancer.

Author information

1
Department of Biosurgery and Surgical Technology, Faculty of Medicine, Imperial College London, London, United Kingdom. p.mintz@imperial.ac.uk

Abstract

BACKGROUND:

Estrogens play a central role in breast cancer development, and the estrogen receptor-alpha (ERalpha) 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 ERalpha-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 ERalpha 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 ERalpha as the in vivo receptor responsible for transcription-independent cellular responses to estrogens.

PMID:
18615623
DOI:
10.1002/cncr.23699
[Indexed for MEDLINE]
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