TY - JOUR
T1 - Estrogen-related receptor α1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway
AU - Ariazi, Eric A.
AU - Kraus, Richard J.
AU - Farrell, Michael L.
AU - Jordan, V. Craig
AU - Mertz, Janet E.
PY - 2007/1
Y1 - 2007/1
N2 - We previously showed that (a) estrogen-related receptor α1 (ERRα1) down-modulates estrogen receptor (ER)-stimulated transcription in low ErbB2-expressing MCF-7 mammary carcinoma cells, and (b) ERRα and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRα1 represses ERα-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERRα1 activated estrogen response element- and ERR response element-mediated transcription in ERα-positive, high ErbB2-expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERRα1 reflected the cell type-specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERRα1. Two-dimensional PAGE of radiophosphate-labeled ERRα1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERRα1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRα1 in vitro. ERRα1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/Akt, with U0126 or LY294002, respectively. Thus, ERRα1 activities are regulated, in part, via ErbB2 signaling, with ERRα1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRα1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal- and ErbB2-based treatment options, with ERRα1 serving as a novel target for drug development.
AB - We previously showed that (a) estrogen-related receptor α1 (ERRα1) down-modulates estrogen receptor (ER)-stimulated transcription in low ErbB2-expressing MCF-7 mammary carcinoma cells, and (b) ERRα and ErbB2 mRNA levels positively correlate in clinical breast tumors. We show here that ERRα1 represses ERα-mediated activation in MCF-7 cells because it failed to recruit the coactivator glucocorticoid receptor interacting protein 1 (GRIP1) when bound to an estrogen response element. In contrast, ERRα1 activated estrogen response element- and ERR response element-mediated transcription in ERα-positive, high ErbB2-expressing BT-474 mammary carcinoma cells, activation that was enhanced by overexpression of GRIP1. Likewise, regulation of the endogenous genes pS2, progesterone receptor, and ErbB2 by ERRα1 reflected the cell type-specific differences observed with our reporter plasmids. Importantly, overexpression of activated ErbB2 in MCF-7 cells led to transcriptional activation, rather than repression, by ERRα1. Two-dimensional PAGE of radiophosphate-labeled ERRα1 indicated that it was hyperphosphorylated in BT-474 relative to MCF-7 cells; incubation of these cells with anti-ErbB2 antibody led to reduction in the extent of ERRα1 phosphorylation. Additionally, mitogen-activated protein kinases (MAPK) and Akts, components of the ErbB2 pathway, phosphorylated ERRα1 in vitro. ERRα1-activated transcription in BT-474 cells was inhibited by disruption of ErbB2/epidermal growth factor receptor signaling with trastuzumab or gefitinib or inactivation of downstream components of this signaling, MAPK kinase/MAPK, and phosphatidylinositol-3-OH kinase/Akt, with U0126 or LY294002, respectively. Thus, ERRα1 activities are regulated, in part, via ErbB2 signaling, with ERRα1 likely positively feedback-regulating ErbB2 expression. Taken together, we conclude that ERRα1 phosphorylation status shows potential as a biomarker of clinical course and antihormonal- and ErbB2-based treatment options, with ERRα1 serving as a novel target for drug development.
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U2 - 10.1158/1541-7786.MCR-06-0227
DO - 10.1158/1541-7786.MCR-06-0227
M3 - Article
C2 - 17259347
AN - SCOPUS:33846951523
SN - 1541-7786
VL - 5
SP - 71
EP - 85
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 1
ER -