Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Hedrick, Erik; Lee, Syng‐Ook; Doddapaneni, Ravi; Singh, Mandip; Safe, Stephen

doi:10.1530/erc-15-0063

Cited by 52 publications

(106 citation statements)

References 42 publications

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“…Therefore, similar to their opposing roles in metabolic reprogramming, ESSRA and ESSRG display opposing influences on breast cancer cell migration and invasiveness. NUR77 NUR77 (NR4A1) expression is elevated in both ER+ and ER− breast tumors (Muscat et al 2013), and NUR77 expression is correlated with decreased relapsefree survival in breast cancer (Alexopoulou et al 2010), consistent with reports of its pro-oncogenic role in breast cancer (Hedrick et al 2015). Contradictory to a previous report of NUR77 having anti-migratory effects in MCF-10A breast cancer cells, recently, NUR77 expression was shown to have pro-migratory effects through activation of TGF-beta signaling (Zhou et al 2014), which is known to have an important role in breast cancer metastasis (Moore et al 2008, Kohn et al 2012, Luwor et al 2015.…”

Section: Estrogen-relatedsupporting

confidence: 80%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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Section: Estrogen-relatedsupporting

confidence: 80%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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“…The cells were visualized by microscopy (Advanced Microscopy), and NR4A1 localization was determined by green fluorescence. DAPI was used to stain the nucleus, and images were taken sequentially of NR4A1, DAPI, and then merged (28)(29)(30).…”

Section: Methodsmentioning

confidence: 99%

“…SKBR3, MDA-MB-231, and MCF-7 cancer cells (3.0 ϫ 10 5 per well) were seeded in Dulbecco's modified Eagle's medium-Ham's F-12 medium supplemented with 2.5% charcoalstripped fetal bovine serum and were allowed to attach for 24 h. The cells were transfected with 100 nM si␤1-integrin, siNR4A1, siSp1, or sip300 for 72 h or treated with various C-DIM compounds. Cell lysates were analyzed by Western blotting as described previously (28)(29)(30).…”

Section: Methodsmentioning

confidence: 99%

“…Small interfering RNA (siRNA) experiments were conducted as described previously (28)(29)(30). The siRNA complexes used in the study are as follows: siGL2-5=, CGU ACG CGG AAU ACU UCG A; siNR4A1, SASI_Hs02_00333289 [1], SASI_Hs02_00333290 [2]; si␤1-integrin, SASI_Hs02_00333437 [1], SASI_Hs01_00159474; siSp1, SASI_Hs02_003; sip300, SASI_Hs01_ 00052818.…”

Section: Methodsmentioning

confidence: 99%

“…Studies in this laboratory have characterized a series of 1,1-bis(3=-indolyl)-1-(p-substituted phenyl) methane (C-DIM) analogs that bind NR4A1 and act as receptor antagonists to inhibit growth and induce apoptosis in several cancer cell lines and in tumors from mouse xenografts (25)(26)(27)(28)(29)(30). A recent study demonstrated functional interactions between NR4A1 and transforming growth factor ␤ (TGF-␤) and in estrogen receptor (ER)-negative MDA-MB-231 cells, knockdown of NR4A1 decreased migration and also inhibited TGF-␤-induced migration of this cell line (31).…”

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confidence: 99%

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NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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cOverexpression 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 ␤ (TGF-␤) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-␤ independent and dependent on regulation of ␤1-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-pPhCO 2 Me)] analog. The NR4A1 antagonists also inhibited TGF-␤-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-␤-induced cell migration. We also observed that NR4A1 regulates expression of both ␤1-and ␤3-integrins, and unlike other ␤1-integrin inhibitors which induce prometastatic ␤3-integrin, NR4A1 antagonists inhibit expression of both ␤1-and ␤3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. Cell adhesion and attachment are essential for tissue integrity and cellular homeostasis, and the heterodimeric integrin cell surface receptors play a critical role in these processes (1-3). There are 18 different ␣ subunits and 8 different ␤ subunits that form 24 ␣␤-integrin receptor heterodimers, and the large 12-member ␤1-integrin subgroup bind multiple extracellular matrix (ECM) molecules to activate multiple intracellular pathways and also induce cross talk with other signaling systems (1-3). The functions of integrin heterodimers are highly tissue specific, and many human pathologies also involve integrin signaling (reviewed in references 4 and 5). ␤1-Integrin is highly expressed in most tumors and is associated with a negative prognostic significance such as overall and disease-free survival, recurrence, and metastasis for head and neck and squamous cell carcinoma, melanoma, lung, breast, prostate, laryngeal, and pancreatic cancers (6-17). A recent immunostaining study of 225 breast invasive ductal carcinomas (IDCs) showed that ␤1-integrin was overexpressed in 32.8% of patients with IDCs (13). Numerous studies show that focal adhesion kinase (FAK) which is downstream from ␤1-integrin is also a negative prognostic factor for breast cancer patients (18)(19)(20). The important functional role of ␤1-integrin has been demonstrated in mouse models expressing erbB2 under the control of the mouse mammary tumor virus and crossed with mammary tissue-specific ␤1-integrin-deficient mice. These mice exhibit a decrease in tumor volume, increased apoptosis, and decreased lung metastasis compared to animals expressing wild-type ␤1-integrin (21-23). Although small molecules, peptides, and antibodies that inhibit ␤1-integrin signaling have been developed, clinical agents that target ␤1-integrin for cancer chemotherapy are not cur...

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The nuclear orphan receptor NR4A1 regulates β1‐integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists

Hedrick

Lee

Safe

2017

Molecular Carcinogenesis

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β1-Integrin is highly expressed and is a negative prognostic factor for colon and pancreatic cancer patients and the gene plays a functional role in cell migration and invasion. In this study, we demonstrate that β1-integrin expression is regulated in pancreatic and colon cancer cells by the pro-oncogenic orphan nuclear receptor 4A1 (NR4A1, Nur77, TR3) and knockdown of this receptor by RNA interference decreases β1-integrin protein and mRNA expression, α5-integrin and also expression of β1-integrin-dependent phosphorylation of FAK (pFak). Knockdown of NR4A1 also decreased migration and fibronectin-induced adhesion in pancreatic (Panc1, L3.6pL and MiaPaCa2) and colon (RKO and SW480) cancer cells. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds containing p-hydroxy (DIM-C-pPhOH) and p-carbomethoxy (DIM-C-pPhCO2Me) groups are NR4A1 ligands that act as antagonists for this receptor. Treatment of pancreatic and colon cancer cells with DIM-C-pPhOH or DIM-C-pPhCO2Me mimics the effects of NR4A1 knockdown and decreases β1-integrin expression, β1-integrin regulated genes and responses including migration and adhesion. The results demonstrate a novel method for targeting β1-integrin in colon and pancreatic cancer cells and indicate possible clinical applications for C-DIM/NR4A1 antagonists for pancreatic and colon cancer therapy.

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Nuclear receptor 4A1 as a drug target for breast cancer chemotherapy

Cited by 52 publications

References 42 publications

Emerging functional roles of nuclear receptors in breast cancer

Emerging functional roles of nuclear receptors in breast cancer

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

The nuclear orphan receptor NR4A1 regulates β1‐integrin expression in pancreatic and colon cancer cells and can be targeted by NR4A1 antagonists

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