FOXP1 enhances tumor cell migration by repression of NFAT1 transcriptional activity in MDA‐MB‐231 cells

Halaçlı, Sevil Oskay

doi:10.1002/cbin.10702

Cited by 22 publications

(18 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While FOXP1 staining was predominantly localized in the nuclei in UDH, the FOXP1 nuclear distribution gradually decreased from ADH, DCIS to IDC, and the cytoplasmic staining increased. These results were consistent with the previous reported heterogeneous expression pattern of FOXP1, in terms of the proportion of positive cells, the staining intensity, and subcellular localization [ 3 , 36 ]. Our observations strongly indicated that FOXP1 expression might shift from the nucleus to the cytoplasm during breast tumorigenesis, and therefore, cytoplasmic mislocalization of FOXP1 is suggested play an important role in breast cancer progression.…”

Section: Discussionsupporting

confidence: 93%

Cytoplasmic FOXP1 expression is correlated with ER and calpain II expression and predicts a poor outcome in breast cancer

Zhou

et al. 2018

Diagn Pathol

View full text Add to dashboard Cite

BackgroundNuclear forkhead box protein P1 (N-FOXP1) expression in invasive breast cancer has been documented in the literature. However, the FOXP1 expression patterns at different stages of breast cancer progression are largely unknown, and the significance of cytoplasmic FOXP1 (C-FOXP1) expression in breast cancer has not been well illustrated. The aims of this study were to investigate FOXP1 expression patterns in invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH) and usual ductal hyperplasia (UDH), and to analyze the clinicopathological relevance of C-FOXP1 and its prognostic value in IDC.MethodsN-FOXP1 and C-FOXP1 expression in cases of IDC, DCIS, ADH and UDH was determined using immunohistochemistry. The correlation between C-FOXP1 expression and clinicopathological parameters as well as the overall survival (OS) and disease-free survival (DFS) rates of patients with IDC were analyzed.ResultsExclusive N-FOXP1 expression was found in 85.0% (17/20), 40.0% (8/20), 12.2% (5/41) and 10.8% (9/83) of UDH, ADH, DCIS, and IDC cases, respectively, and exclusive C-FOXP1 expression was observed in 0% (0/20), 0% (0/20), 4.9% (2/41), and 31.3% (26/83) of the cases, respectively. Both N- and C-FOXP1 staining were observed in 15.0% (3/20), 60.0% (12/20), 82.9% (34/41) and 48.2% (40/83) of the above cases, respectively, while complete loss of FOXP1 expression was observed in only 9.6% (8/83) of IDC cases. Estrogen receptor (ER) expression in C-FOXP1-positive IDC cases (31/66, 47.0%) was significantly lower than that in C-FOXP1-negative cases (13/17, 76.5%) (p = 0.030). Calpain II expression was observed in 83.3% (55/66) of C-FOXP1-positive IDC cases, which was significantly higher than that in C-FOXP1-negative cases (9/17, 52.9%) (p = 0.007). Calpain II was significantly associated with pAKT (p = 0.029), pmTOR (p = 0.011), p4E-BP1 (p < 0.001) and p-p70S6K (p = 0.003) expression levels. The 10-year OS and DFS rates of the C-FOXP1-positive patients were 60.5% and 48.7%, respectively, both of which were lower than those of the C-FOXP1-negative patients (93.3, 75.3%). The OS curve showed a dramatic impact of C-FOXP1 status on OS (p = 0.045).ConclusionsCytoplasmic relocalization of FOXP1 protein was a frequent event in breast IDC. Calpain II might play an important role in nucleocytoplasmic trafficking of FOXP1 and the AKT pathway might be involved in this process. C-FOXP1 expression was inversely associated with ER expression and might be a predictor of poor OS in patients with IDC.

show abstract

Section: Discussionsupporting

confidence: 93%

Cytoplasmic FOXP1 expression is correlated with ER and calpain II expression and predicts a poor outcome in breast cancer

Zhou

et al. 2018

Diagn Pathol

View full text Add to dashboard Cite

show abstract

“…We thus decided to focus our investigations on FOXP1, a winged helix/forkhead transcription factor that has been associated with normal and cancer stem cell function ( Choi et al., 2016 , Gabut et al., 2011 , Naudin et al., 2017 ). Intriguingly, FOXP1 is generally considered a tumor suppressor in the breast because high levels correlate with better prognosis, despite the finding that it promotes proliferation and migration of breast cancer cell lines ( Oskay Halacli, 2017 , Shigekawa et al., 2011 , Xiao et al., 2016 ). Because of this apparent contradiction and link with stem cell biology ( Choi et al., 2016 , Gabut et al., 2011 ), we decided to investigate the relationship between PRMT5, FOXP1, and BCSC function in more detail.…”

Section: Resultsmentioning

confidence: 99%

PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

et al. 2017

View full text Add to dashboard Cite

SummaryBreast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.

show abstract

“…Interestingly, a recent study indicated that the majority of invasive breast cancers (67%, n = 133) showed a nuclear immunoreactivity of the estrogen-inducible FOXP1 51 , whereby knockdown of FOXP1 suppressed and ectopic expression promoted breast cancer cell proliferation. FOXP1 also enhanced the migration of MDA-MB-231 metastatic breast cancer cells via transcriptional repressing of NFAT1 52 . The evidence presented in the current study indicated a negative regulation of HDAC4 and FOXP1 by miR-22 in fulvestrant-resistant breast cancer cells, which supports previous reports showing that HDAC4 and FOXP1 were direct targets of miR-22 49 , 50 .…”

Section: Discussionmentioning

confidence: 95%

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

Wang

Filkowski

et al. 2018

Oncogenesis

View full text Add to dashboard Cite

Antiestrogen resistance is a major challenge encountered during the treatment of estrogen receptor alpha positive (ERα+) breast cancer. A better understanding of signaling pathways and downstream transcription factors and their targets may identify key molecules that can overcome antiestrogen resistance in breast cancer. An aberrant expression of miR-22 has been demonstrated in breast cancer; however, its contribution to breast cancer resistance to fulvestrant, an antiestrogen drug, remains unknown. In this study, we demonstrated a moderate elevation in miR-22 expression in the 182R-6 fulvestrant-resistant breast cancer line we used as a model system, and this elevation was positively correlated with the expression of the miRNA biogenesis enzymes AGO2 and Dicer. The level of phosphorylated HER2/neu at Tyr877 was also upregulated in these cells, whereas the level of RelA/p65 phosphorylated at Ser536 (p-p65) was downregulated. Knockdown of HER2/neu led to an induction of p-p65 and a reduction in miR-22 levels. Luciferase assays identified two NF-κB binding motifs in the miR-22 promoter that contributed to transcriptional repression of miR-22. Activation of RelA/p65, triggered by LPS, attenuated miR-22 expression, but this expression was restored by sc-514, a selective IKKβ inhibitor. Inhibition of miR-22 suppressed cell proliferation, induced apoptosis and caused cell cycle S-phase arrest, whereas enhancing expression of p21Cip1/Waf1 and p27Kip1. Surprisingly, ectopic expression of miR-22 also suppressed cell proliferation, induced apoptosis, caused S-phase arrest, and promoted the expression of p21Cip1/Waf1 and p27Kip1. Ectopic overexpression of miR-22 repressed the expression of FOXP1 and HDAC4, leading to a marked induction of acetylation of HDAC4 target histones. Conversely, inhibition of miR-22 promoted the expression of both FOXP1 and HDAC4, without the expected attenuation of histone acetylation. Instead, p53 acetylation at lysine 382 was unexpectedly upregulated. Taken together, our findings demonstrated, for the first time, that HER2 activation dephosphorylates RelA/p65 at Ser536. This dephosphoryalted p65 may be pivotal in transactivation of miR-22. Both increased and decreased miR-22 expression cause resensitization of fulvestrant-resistant breast cancer cells to fulvestrant. HER2/NF-κB (p65)/miR-22/HDAC4/p21 and HER2/NF-κB (p65)/miR-22/Ac-p53/p21 signaling circuits may therefore confer this dual role on miR-22 through constitutive transactivation of p21.

show abstract

FOXP1 enhances tumor cell migration by repression of NFAT1 transcriptional activity in MDA‐MB‐231 cells

Cited by 22 publications

References 53 publications

Cytoplasmic FOXP1 expression is correlated with ER and calpain II expression and predicts a poor outcome in breast cancer

Cytoplasmic FOXP1 expression is correlated with ER and calpain II expression and predicts a poor outcome in breast cancer

PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

Contact Info

Product

Resources

About