TY - JOUR
T1 - Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor positive breast cancer cells
AU - Hostetter, Christine
AU - Licata, Lauren A.
AU - Witkiewicz, Agnieszka
AU - Costantino, Christina L.
AU - Yeo, Charles J.
AU - Brody, Jonathan R.
AU - Keen, Judith Clancy
N1 - Funding Information:
©2008 LANDES BIOSCIENCEto thank Drs. Neil Clancy y the UMDNJ Foundation
PY - 2008/9
Y1 - 2008/9
N2 - With prolonged exposure, a majority of estrogen receptor positive cancers develop resistance to tamoxifen and subsequent therapies including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). While much is known about overexpression of key growth promoting receptors including EGF, erbB2/ Her2 and IGF receptors and subsequent activation of MAPK signaling associated with resistance, the underlying mechanism in the development of resistance still remains unknown. We found that inhibition of JNK, a member of the MAPK family, decreases cytoplasmic accumulation of the RNA binding protein HuR. This data combined with previous reports that erbB2/Her2 and IGF-IR signals through JNK, led us to hypothesize that cytoplasmic accumulation of HuR may be a key contributor to development of tamoxifen resistance. Therefore, we tested the effect of HuR expression on tamoxifen responsiveness in both tamoxifen sensitive MCF7 and tamoxifen resistant BT474 cell lines. We found that decreasing the cytoplasmic HuR levels in the cells increases tamoxifen responsiveness in both cell lines. Conversely, the overexpression of HuR establishes tamoxifen resistance in MCF7 cells. Therefore, our data indicate that HuR is central to tamoxifen resistance. Interestingly, we found that acute exposure (24 and 48 h) of MCF7 cells to tamoxifen increased cytoplasmic levels of HuR and concomitantly it's ligand pp32, suggesting a novel molecular mechanism of resistance and acute response to tamoxifen through increased stability of mRNA transcripts that code for drug-resistant transcripts. Indeed, evaluation of primary breast tumors revealed a correlation between tumor grade, tamoxifen responsiveness and cytoplasmic HuR status. Therefore, inhibition of the cytoplasmic accumulation of HuR concomitantly with the administration of current therapeutics may be a successful treatment strategy. Our data describe a novel mechanism for the development of tamoxifen resistance and is the first study to identify an RNA binding protein as a key mediator of resistance in breast cancer cells.
AB - With prolonged exposure, a majority of estrogen receptor positive cancers develop resistance to tamoxifen and subsequent therapies including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). While much is known about overexpression of key growth promoting receptors including EGF, erbB2/ Her2 and IGF receptors and subsequent activation of MAPK signaling associated with resistance, the underlying mechanism in the development of resistance still remains unknown. We found that inhibition of JNK, a member of the MAPK family, decreases cytoplasmic accumulation of the RNA binding protein HuR. This data combined with previous reports that erbB2/Her2 and IGF-IR signals through JNK, led us to hypothesize that cytoplasmic accumulation of HuR may be a key contributor to development of tamoxifen resistance. Therefore, we tested the effect of HuR expression on tamoxifen responsiveness in both tamoxifen sensitive MCF7 and tamoxifen resistant BT474 cell lines. We found that decreasing the cytoplasmic HuR levels in the cells increases tamoxifen responsiveness in both cell lines. Conversely, the overexpression of HuR establishes tamoxifen resistance in MCF7 cells. Therefore, our data indicate that HuR is central to tamoxifen resistance. Interestingly, we found that acute exposure (24 and 48 h) of MCF7 cells to tamoxifen increased cytoplasmic levels of HuR and concomitantly it's ligand pp32, suggesting a novel molecular mechanism of resistance and acute response to tamoxifen through increased stability of mRNA transcripts that code for drug-resistant transcripts. Indeed, evaluation of primary breast tumors revealed a correlation between tumor grade, tamoxifen responsiveness and cytoplasmic HuR status. Therefore, inhibition of the cytoplasmic accumulation of HuR concomitantly with the administration of current therapeutics may be a successful treatment strategy. Our data describe a novel mechanism for the development of tamoxifen resistance and is the first study to identify an RNA binding protein as a key mediator of resistance in breast cancer cells.
KW - 5-aza 2′ deoxycytidine
KW - Estrogen receptor
KW - HuR
KW - Tamoxifen resistance
KW - Trichostatin A
KW - pp32
UR - http://www.scopus.com/inward/record.url?scp=58149172080&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149172080&partnerID=8YFLogxK
U2 - 10.4161/cbt.7.9.6490
DO - 10.4161/cbt.7.9.6490
M3 - Article
C2 - 18769129
AN - SCOPUS:58149172080
SN - 1538-4047
VL - 7
SP - 1496
EP - 1506
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 9
ER -