PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

Ito, Koichi; Park, Sun Hee; Nayak, Anupma; Byerly, Jessica H.; Irie, Hanna Y.

doi:10.1158/0008-5472.can-15-3445

Cited by 54 publications

(66 citation statements)

References 53 publications

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“…2c), suggesting that ERβ1 promoted cell-cell adhesion by regulating the expression of E-cadherin and N-cadherin. Several transcription factors, such as Snail, Twist and ZEB1, had been reported to promote EMT in multiple tumors, including breast cancer [23, 24]. For example, BCL6 induced EMT by promoting the ZEB1-mediated transcription repression of E-cadherin in breast cancer cells.…”

Section: Resultsmentioning

confidence: 99%

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ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

Song

Tang

et al. 2017

J Exp Clin Cancer Res

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BackgroundIncreasing evidence has indicated an important role for estrogen receptor beta 1 (ERβ1) in breast cancer. However, the role of ERβ1 in the metastasis of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) and the underlying mechanisms are still unknown.MethodsStable ERβ1-expressing TNBC cell lines were generated for this study. We detected the abilities of cell migration and invasion by wound-healing and transwell assays and the expression of E-cadherin and N-cadherin by quantitative RT-PCR (qRT-PCR) and western blotting assays in TNBC cell lines. Chromatin immunoprecipitation (ChIP) analysis was performed to assess the effect of AR on ERβ1 promoter. Tumor metastasis was evaluated in vivo using a lung metastasis mouse model. Lastly, immunohistochemical expression of ERβ1 in TNBC tissues was analyzed and correlated with clinicopathological features.ResultsERβ1 suppressed the invasion and migration abilities of AR-positive TNBC cells and induced the downregulation of ZEB1. ZEB1 overexpression abrogated the increase in E-cadherin expression and the decrease in N-cadherin expression modulated by ERβ1. A lung metastasis mouse model showed that the incidence of metastasis was lower in ERβ1-expressing TNBC cells. Further, AR activation increased the anti-metastatic effect of ERβ1 in AR-positive TNBC cells, which accelerated ERβ1 transcription by functioning as a transcription factor that bound to the promoter of ERβ1. No significant change was observed in AR expression induced by ERβ1. Immunohistochemistry (IHC) analysis of TNBC clinical samples showed that ERβ1 and AR were positive in 31.7% and 23.2% of samples, respectively. ERβ1 expression was negatively correlated with ZEB1 expression and lymph node metastasis, and positively correlated with the expression of AR and E-cadherin.ConclusionOur findings suggested a potential role of ERβ1 in metastasis of AR-positive TNBC and provided novel insights into the mechanism of action of ERβ1 and the possible relationship between ERβ1 and AR.

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Section: Resultsmentioning

confidence: 99%

“…The expression of EMT markers, such as E-cadherin and N-cadherin, has been reported to correlate with tumor metastasis [32, 33]. For example, PTK6 inhibition suppresses metastases of TNBC via Snail-dependent E-cadherin regulation [23]. We examined if ERβ1 inhibits invasion and migration by regulating EMT markers.…”

Section: Discussionmentioning

confidence: 99%

ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

Song

Tang

et al. 2017

J Exp Clin Cancer Res

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“…Due to the incomplete elucidation of the molecular profile of TNBCs metastases, a standardized therapy is not yet available in clinical practice. However, protein tyrosine kinase 6 (PTK6), a protein tyrosine kinase expressed in approximately 70% of TNBCs, may constitute a potential target for metastases suppression [88]. Also, the metastatic potential of TNBCs may be successfully reduced through metastasis-associated phosphatase of regenerating liver-3 (PRL-3) blocking, a metastasis-promoting phosphatase [89].…”

Section: Targeted Therapy In Tnbcsmentioning

confidence: 99%

Triple negative breast cancer: the kiss of death

et al. 2017

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One of the most controversial women malignancies, triple negative breast cancers (TNBCs) are critically overviewed here, being focused on data useful in clinical practice or to improve the therapy and patients survival. TNBCs “choose” young women and its “kiss” is, unfortunately deadly in most cases. Currently, few sparse data are available in literature concerning the origins of TNBC. Vasculogenic mimicry detected in TNBCs, seems to be determined by a population of CD133+ cells and may be stimulated by different pharmacological agents such sunitinib. Despite the fact that TNBCs do not usually metastasize through the lymphatic pathways, TNBCs may be characterized by lymphatic invasion and by an increased lymphatic microvascular density. If TNBCs treatment depends on the molecular profile of the tumor, the same statement may be postulated for TNBCs metastasis. Whether metastases have a similar phenotype as the primary tumor remains an enigma. Therefore, the question: ‘Could TNBC be subject to a standardized, unanimously accepted therapeutic strategy or is it strictly subclass-dependent?’ remains to be further investigated.

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“…The EMT process is triggered by its specific activators, such as Slug, Snail, Twist, or ZEB1 (38)(39)(40). During the EMT process, a crucial change is the downregulation of E-cadherin expression, which indicates that cells are losing their epithelial traits (41,42). Meanwhile, the expression of mesenchymal markers, such as N-cadherin and vimentin, are upregulated (43)(44)(45)(46).…”

Section: Introductionmentioning

confidence: 99%

STAT3 Targets ERR-α to Promote Epithelial–Mesenchymal Transition, Migration, and Invasion in Triple-Negative Breast Cancer Cells

Lin

et al. 2019

Molecular Cancer Research

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STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor a (ERR-a) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-a promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-a, and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation assay. We also found that ERR-a was the key target gene regulated by STAT3 in promoting epithelial-mesenchymal transition (EMT), migration, and invasion. ERR-a upregulated the expression of ZEB1, N-cadherin, and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-a could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-a was a direct regulatory gene target of p-STAT3, which was enriched for processes involving invasion and metastasis in TNBC and provided insight into TNBC pathogenesis, as well as a potential therapeutic option against TNBC metastasis. Implications: Our research first showed that p-STAT3 (Tyr 705) could bind to the promotor region of ERR-a and promote EMT in TNBC by ZEB1 pathways, thus providing a potential clinical target for TNBC.

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PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

Cited by 54 publications

References 53 publications

ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

ERβ1 inhibits metastasis of androgen receptor-positive triple-negative breast cancer by suppressing ZEB1

Triple negative breast cancer: the kiss of death

STAT3 Targets ERR-α to Promote Epithelial–Mesenchymal Transition, Migration, and Invasion in Triple-Negative Breast Cancer Cells

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