Estrogen activation of the mitogen-activated protein kinase is mediated by ER-α36 in ER-positive breast cancer cells

XinTian Zhang, Hao Deng, Zhao-Yi Wang
Journal of Steroid Biochemistry and Molecular Biology 2014, 143: 434-43
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.

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