The Role of the Hippo Pathway in Breast Cancer Carcinogenesis, Prognosis, and Treatment: A Systematic Review

Kyriazoglou, Anastasios; Liontos, Michalis; Zakopoulou, Roubini; Kaparelou, Maria; Tsiara, Anna; Papatheodoridi, Alkistis; Georgakopoulou, Rebecca; Zagouri, Flora

doi:10.1159/000507538

Cited by 19 publications

(28 citation statements)

References 92 publications

(145 reference statements)

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“…These ndings are in accordance with previous publications showing that PABC are commonly tumors with low HR status [16,18]. Additionally, our data confer a possibly crucial molecular mechanism for the development of a subset of PABC, which generally are shown to have complex genetic and molecular background [8,15].…”

Section: Discussionsupporting

confidence: 93%

“…When the abovementioned pathway is switched off though, the Hippo key transducers TAZ and YAP1 translocate to the nucleus combining with the TEAD (transcriptional enhanced associated domain) transcription factors 1-4, thus demonstrating signi cant oncogenic function [5,6]. Multiple theories have evolved regarding Hippo signaling de-regulation and cross talking with several pathways (e.g., Wnt/β-catenin, TGF-β, JNK) leading to carcinogenesis, metastasis, and drug resistance [7,8]. Additionally, the Hippo signaling pathway has been extensively explored in various tumors including metastatic breast cancer, triplenegative breast cancer (TNBC), and male breast cancer [7,9,10].…”

Section: Introductionmentioning

confidence: 99%

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Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-Associated Breast Cancer Tumorigenesis

Kyriazoglou

Korakiti

Papatheodoridi

et al. 2021

Preprint

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Background: Hippo signaling pathway de-regulation has been strongly associated with tumorigenesis, metastasis, and drug resistance. Pregnancy-associated breast cancer, the most frequently diagnosed malignancy during gestation, demonstrates an intricate molecular nature. The aim of the present study is to evaluate Hippo pathway transducers TAZ and YAP1 expression in pregnancy-associated breast cancer in relation to the clinicopathological characteristics of the disease.Methods: Formalin-fixed paraffin-embedded tissues from 21 PABC patients treated at Alexandra Hospital in Athens, Greece were immunohistochemically analyzed. Statistical analysis was performed to investigate a possible correlation among the Hippo pathway signaling and the clinical features of the disease.Results: In 48% of patients included in the study strong nuclear TAZ/YAP1 staining in tumor cells was identified. Additionally, the hormone receptor negative status was statistically correlated with strong positivity of the TAZ/YAP1 co-transcriptional factors. No association was observed with the overall-survival and the disease-free survival rate. Conclusions: Hippo pathway is proven to be de-regulated in a subset of pregnancy-associated breast cancer patients highlighting the complex molecular background of the disease which certainly requires further investigation.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-Associated Breast Cancer Tumorigenesis

Kyriazoglou

Korakiti

Papatheodoridi

et al. 2021

Preprint

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“…Of note, in our study, low KIBRA expression was also significantly associated with high-grade morphologic features, which is consistent with the characteristics of patients with ER-negative breast cancer, especially TNBC. Much of the premise for KIBRA as a tumor suppressor comes from its role in activating the Hippo signaling pathway, for which loss of function and the concomitant activation of YAP/TAZ are well-documented in TNBCs [ 24 ]. The role of KIBRA in suppressing mechanical signals activating TAZ may be related to the suppression of self-renewal, given that an undifferentiated stem-like state is maintained through contact with the extracellular matrix [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…The Hippo signaling pathway is a pathway that has recently been said to have several oncogenic functions in breast cancer [ 28 ]. Hippo molecular elements—KIBRA, YAP/TAZ, Aurora kinase, and LATS—have been shown to participate in breast cancer development through different mechanisms, resulting in different roles among its molecular subtypes [ 24 ]. In particular, among molecular subtypes, chromosome 5q loss is detected in 70% of TNBC, which involves the Hippo molecular element, KIBRA, a major factor contributing to its effects on tumor growth and metastatic progression.…”

Section: Discussionmentioning

confidence: 99%

Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Kim

Chu

et al. 2021

Medicina

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Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

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“…YAP1, which is involved in the Hippo signaling pathway, has been reported to be upregulated in osteosarcoma and associated with a poor prognosis (13). Several oncogenic pathways feed into the Hippo signaling pathway in a YAP1-dependent Verteporfin suppresses osteosarcoma progression by targeting the Hippo signaling pathway manner, such as Wnt/β-catenin, PI3K/AKT, MAPK and JAK/STAT signaling pathways (14). YAP1-mediated oncogenic effects are dependent on TEADs (15).…”

Section: Introductionmentioning

confidence: 99%

Verteporfin suppresses osteosarcoma progression by targeting the Hippo signaling pathway

Yang

Jiang

et al. 2021

Oncol Lett

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Verteporfin (VP) is a specific inhibitor of yes-associated protein 1 (YAP1) that suppresses tumor progression by inhibiting YAP1 expression. The present study aimed to determine the inhibitory effect of VP on osteosarcoma and the underlying mechanism of its anticancer effects. Cell viability, cell cycle and apoptosis and cell migration and invasion were analyzed using the MTT assay, flow cytometry, wound healing assay and Transwell assay, respectively. Expressions of YAP1 and TEA domain transcription factor 1 (TEAD1) were measured using reverse transcription-quantitative PCR and western blotting, while their interaction was identified by the co-immunoprecipitation assay. In vivo mouse xenograft experiments were performed to evaluate the effect of VP on osteosarcoma growth. The results demonstrated that YAP1 and TEAD1 were highly expressed in osteosarcoma cells and tissues, whereas VP significantly downregulated the expression levels of YAP1 and TEAD1 in the osteosarcoma cell line Saos-2 compared with those in untreated control cells. In addition, compared with those in the control group, VP suppressed the viability, migration and invasion, induced cell cycle arrest in the G1 phase and promoted apoptosis in Saos-2 cells. In addition, VP inhibited mouse xenograft tumor growth in vivo compared with that observed in the control group. Notably, VP downregulated the levels of CYR61 expression in Saos-2 cells, whereas CYR61 overexpression mitigated the inhibitory effects of VP on osteosarcoma cells, as indicated by the increased viability and reduced apoptotic rates in Saos-2 cells overexpressing CYR61 compared with those in the control group. In summary, VP suppressed osteosarcoma by downregulating the expression of YAP1 and TEAD1. Additionally, CYR61 may mediate the effects of VP on osteosarcoma progression.

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The Role of the Hippo Pathway in Breast Cancer Carcinogenesis, Prognosis, and Treatment: A Systematic Review

Cited by 19 publications

References 92 publications

Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-Associated Breast Cancer Tumorigenesis

Chasing Hippos: Implications of YAP1 and TAZ Expression in Pregnancy-Associated Breast Cancer Tumorigenesis

Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Verteporfin suppresses osteosarcoma progression by targeting the Hippo signaling pathway

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