Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Greco, Maria Raffaella; Bon, Émeline; Rubino, Rosa; Guerra, Lorenzo; Bernabé-García, Manuel; Cannone, Stefania; Cayuela, Maria-Luisa; Ciaccia, Loredana; Marionneau-Lambot, Séverine; Oullier, Thibauld; Fromont, Gaëlle; Guibon, Roseline; Roger, Sébastien; Reshkin, Stephan J.; Cardone, Rosa Angela

doi:10.1016/j.bbadis.2018.10.017

Cited by 7 publications

(9 citation statements)

References 71 publications

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“…This structure makes NHERF1 a sticky protein, able to interact with various signal molecules and implicated in different diseases [3]. In the last decade, a lot of studies highlighted its involvement during carcinogenesis and tumor progression [4,5,6,7,8,9], in particular, in BC [10,11,12]. A previous study, which we carried out demonstrated the prognostic significance of nuclear NHERF1 expression (nNHERF1) in a cohort of patients with primary BC [13].…”

Section: Introductionmentioning

confidence: 99%

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

Saponaro

Scarpi

Zito

et al. 2019

Cancers

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The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (β-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients’ clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) and protein localization by immunofluorescence. We found a significant correlation between NHERF1 and FZD4, LRP5, LRP6, and TCF1. Univariate analysis showed that the overexpression of β-catenin (p < 0.0001), FZD4 (p = 0.0001), LRP5, LRP6, and TCF1 (p < 0.0001 respectively) was related to poor disease-free survival (DFS). A Kaplan-Meier analysis confirmed univariate data and showed a poor DFS for cNHERF1+/FZD4+ (p = 0.0007), cNHERF1+/LRP5+ (p = 0.0002), cNHERF1+/LRP6+ (p < 0.0001), and cNHERF1+/TCF1+ phenotypes (p = 0.0034). In multivariate analysis, the expression of TCF1 and β-catenin was an independent prognostic variable of worse DFS (p = 0.009 and p = 0.027, respectively). In conclusion, we found that the overexpression of β-catenin, FZD4, LRP5, LRP6, and TCF1 was associated with poor prognosis. Furthermore, we first identified TCF1 as an independent prognostic factor of poor outcome, indicating it as a new potential biomarker for the management of BC patients. Also, the expression of Wnt pathway proteins, both alone and in association with NHERF1, suggests original associations of biological significance for new studies.

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Section: Introductionmentioning

confidence: 99%

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

Saponaro

Scarpi

Zito

et al. 2019

Cancers

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“…NHERF1 phosphorylation is also essential for tumor-induced angiogenesis (21). In contrast, there were opposite results of either S279 or S301 phosphorylation on anchorage-independent breast cancer cell colony growth and three-dimensional spheroid growth (21). The differential phosphorylation of NHERF1 resulted in differential activation of phosphatase and tensin homolog, Akt, and ERK1/2, consistent with the role for NHERF1 in assembling signaling complexes.…”

Section: Cancermentioning

confidence: 81%

“…NHERF1 has been implicated in the development of metastatic cell behavior (10). Differential phosphorylation of NH-ERF1 is a potential mechanism by which NHERF1 creates distinct protein complexes that either activate or inactivate pathways that promote metastatic behavior (21). The cell functions associated with the metastatic phenotype were enhanced by NHERF1 overexpression and mitigated by mutation of the NHERF1 phosphorylation sites S279 or S301.…”

Section: Cancermentioning

confidence: 99%

“…The cell functions associated with the metastatic phenotype were enhanced by NHERF1 overexpression and mitigated by mutation of the NHERF1 phosphorylation sites S279 or S301. NHERF1 phosphorylation is also essential for tumor-induced angiogenesis (21). In contrast, there were opposite results of either S279 or S301 phosphorylation on anchorage-independent breast cancer cell colony growth and three-dimensional spheroid growth (21).…”

Section: Cancermentioning

confidence: 99%

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New roles of the Na⁺/H⁺ exchange regulatory factor 1 scaffolding protein: a review

Bushau-Sprinkle

Lederer

2020

American Journal of Physiology-Renal Physiology

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Na+/H+ exchange regulatory factor 1 (NHERF1), a member of a PDZ scaffolding protein family, was first identified as an organizer of membrane-bound protein complexes composed of hormone receptors, signal transduction pathways, and electrolyte and mineral transporters and channels. NHERF1 is involved in the regulation of Na+/H+ exchanger 3, Na+-dependent phosphate transporter 2a, and Na+-K+-ATPase through its ability to scaffold these transporters to the plasma membrane, allowing regulation of these protein complexes with their associated hormone receptors. Recently, NHERF1 has received increased interest in its involvement in a variety of functions, including cell structure and trafficking, tumorigenesis and tumor behavior, inflammatory responses, and tissue injury. In this review, we highlight the evidence for the expansive role of NHERF1 in cell biology and speculate on the implications for renal physiology and pathophysiology.

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“…VM channels function similarly to tumor vascular angiogenesis formed by endothelial cells in promoting tumor growth and development 5 . The presence of VM, which is related to tumor stemness and plasticity, 6 is mostly seen in highly invasive tumors, including melanoma, 7 non‐small‐cell lung cancer (NSCLC), 8 breast cancer, 9 and glioblastoma 10 . The presence of VM is considered to be one of the reasons why antitumor angiogenesis therapies fail to achieve the desired results in treatment of these highly aggressive tumors 11 …”

Section: Introductionmentioning

confidence: 99%

DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

Gong

Wang

et al. 2020

J of Cellular Biochemistry

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Angiogenesis and vasculogenic mimicry (VM) are the main causes of tumor metastasis and recurrence. In this study, we investigated the antiangiogenesis and anti-VM formation of a novel microtubule depolymerizing agent, DHPAC, as well as combretastatin A4 (CA4, a combretastatin derivate) in non-small-cell lung cancer (NSCLC), subsequently elucidating the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), DHPAC could enter cells and inhibit proliferation, migration, and angiogenesis in the presence and absence of conditioned medium from H1299 cells. Interestingly, the inhibition was enhanced under the stimulation of the conditioned medium. Under hypoxia or normoxia, DHPAC suppressed signal transducer and activator of transcription 3 phosphorylation and reduced vascular endothelial growth factor (VEGF) expression and secretion from HUVECs, thus impeding the activation of the downstream signal transduction pathway of VEGF/VEGFR2. However, JNK inhibitors reversed the inhibitory effect of DHPAC on the angiogenesis, suggesting that DHPAC regulated angiogenesis through activating JNK. In H1299 cells, DHPAC could inhibit proliferation, migration, invasion, and the formation of VM. In addition, DHPAC inhibited the phosphorylation of FAK and AKT and decreased the expressions of VEGF, matrix metalloproteinase 2 (MMP2), MMP9 and Laminin 5, suggesting that DHPAC inhibited VM formation via the FAK/AKT signaling pathway. In addition, CA4 showed a similar effect as DHPAC against angiogenesis and VM formation. These new findings support the use of microtubule destabilizing agents as a promising strategy for cancer therapy.

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Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Cited by 7 publications

References 71 publications

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

New roles of the Na⁺/H⁺ exchange regulatory factor 1 scaffolding protein: a review

DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

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Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Cited by 7 publications

References 71 publications

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients

New roles of the Na+/H+ exchange regulatory factor 1 scaffolding protein: a review

DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

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New roles of the Na⁺/H⁺ exchange regulatory factor 1 scaffolding protein: a review