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

AbstractBACKGROUND:
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.
AuthorsPaul J Mintz, Nagy A Habib, Louise J Jones, Georgios Giamas, Jacqueline S Lewis, Rebecca L Bowen, R Charles Coombes, Justin Stebbing
JournalCancer (Cancer) Vol. 113 Issue 6 Pg. 1489-95 (Sep 15 2008) ISSN: 0008-543X [Print] United States
PMID18615623 (Publication Type: Journal Article)
Copyright(c) 2008 American Cancer Society.
Chemical References
  • BAD protein, human
  • BCL2L1 protein, human
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
Topics
  • Aged
  • Aged, 80 and over
  • Apoptosis (physiology)
  • Breast (metabolism, pathology)
  • Breast Neoplasms (metabolism, pathology)
  • Carcinoma, Ductal, Breast (metabolism, pathology)
  • Carcinoma, Intraductal, Noninfiltrating (metabolism, pathology)
  • Cell Membrane (metabolism, pathology)
  • Cytoplasm (metabolism, pathology)
  • Cytosol (metabolism, pathology)
  • Estrogen Receptor alpha (metabolism)
  • Estrogens (pharmacology)
  • Female
  • Humans
  • Immunoprecipitation
  • Middle Aged
  • Mitogen-Activated Protein Kinases (metabolism)
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Signal Transduction
  • Tumor Cells, Cultured
  • bcl-Associated Death Protein (metabolism)
  • bcl-X Protein (metabolism)

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