TY - JOUR
T1 - NR4A1 antagonists inhibit β1-integrin-dependent breast cancer cell migration
AU - Hedrick, Erik
AU - Lee, Syng Ook
AU - Doddapaneni, Ravi
AU - Singh, Mandip
AU - Safe, Stephen
N1 - Funding Information:
This work, including the efforts of Mandip Singh, was funded by DOD | Congressionally Directed Medical Research Programs (CDMRP) (BC103116). This work, including the efforts of Stephen Safe, was funded by HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) (P30-ES023512). This work, including the efforts of Stephen Safe, was funded by Texas AgriLife Research.
Publisher Copyright:
© 2016, American Society for Microbiology.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.
AB - Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis.
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U2 - 10.1128/MCB.00912-15
DO - 10.1128/MCB.00912-15
M3 - Article
C2 - 26929200
AN - SCOPUS:84965105056
SN - 0270-7306
VL - 36
SP - 1383
EP - 1394
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 9
ER -