title: Estrogen activation of the mitogen-activated protein kinase is mediated by ER-α36 in ER-positive breast cancer cells.
abstract: It is well known that there are two estrogen-signaling pathways, genomic estrogen signaling and non-genomic or rapid estrogen signaling. Although both ER-α and ER-β have been suggested to mediate both genomic and non-genomic estrogen signaling, rapid estrogen signaling such as activation of the MAPK/ERK signaling in ER-positive breast cancer MCF7 cells has been controversial. Previously, our laboratory cloned a 36kDa variant of ER-α, ER-α36, that is mainly localized at the plasma membrane and is able to mediate rapid estrogen signaling. In this study, we investigated the function and the underlying mechanisms of ER-α36 in rapid estrogen signaling of ER-positive breast cancer cells. ER-positive breast cancer cells MCF7, T47D and H3396 as well as their variants with different levels of ER-α and ER-α36 expression were used to examine estrogen induction of the MAPK/ERK1/2 signaling. The underlying mechanisms were also studied in these cells with the neutralizing antibodies and chemical inhibitors against different growth factors and their receptors. We found that ER-α36 mediated estrogen induction of the MAPK/ERK phosphorylation in ER-positive breast cancer cells while the full-length ER-α failed to do so. The rapid estrogen signaling mediated by ER-α36 involved a orchestrated action of matrix metalloproteinases (MMPs), heparin-binding epidermal growth factor (HB-EGF), amphiregulin, insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), HER2/Neu and Src. Our results thus indicated that ER-α36 is the estrogen receptor that mediates estrogen induction of the MAPK/ERK signaling in ER-positive breast cancer cells.
authors: Departments of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE, USA.
authors: XinTian
authors: X
authors: Zhang
authors: Departments of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE, USA.
authors: Hao
authors: H
authors: Deng
authors: Departments of Medical Microbiology and Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE, USA. Electronic address: zywang@creighton.edu.
authors: Zhao-Yi
authors: ZY
authors: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C506487:ESR1 protein, human
keywords: Amphiregulin; EGFR; ER-α36; ERK1/2; HB-EGF; HER2; IGF-IR; Rapid estrogen signaling