Determination of β-catenin Expression in Breast Cancer and Its Relationship with Clinicopathologic Parameters

Sefidbakht, Sepideh; Saeedipour, Hanieh; Saffar, Hiva; Mirzaian, Elham

doi:10.31557/apjcp.2021.22.11.3493

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…Phosphorylation of IRS-1 stimulates PI3K/Akt signaling that plays a pivotal role in cell proliferation, cell survival, migration, and differentiation [66]. Inappropriate activation of PI3K/Akt signaling has been reported in diverse malignancies including breast cancer [67][68][69]. Our findings indicate that in obese breast tumors, PI3K stimulates PDK1, which phosphorylates Akt kinase.…”

Section: Discussionsupporting

confidence: 57%

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

Kallamadi,

Esari,

Addi

et al. 2023

IJMS

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Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.

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Section: Discussionsupporting

confidence: 57%

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

Kallamadi,

Esari,

Addi

et al. 2023

IJMS

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“…In gastric cancer cells, overexpression of HER2 was shown to increase the stemness and invasiveness, which is regulated by Wnt/β-catenin signaling (Jung et al, 2019). Previously the aberrant expression of β-catenin was associated with more aggressive behaviors of BC although it was not statistically correlated to HER2 (Sefidbakht et al, 2021). However, in epithelial ovarian cancer (EOC), high expression of β-catenin was found in HER2-positive EOC tissue samples and was correlated with a poor patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that Wnt/β-catenin signaling pathway is abnormally activated in human cancers, including BC (Brennan & Brown, 2004;Song et al, 2016). Alternation of β-catenin expression may result from mutation and amplification, both of them lead to the occurrence and progression of BC (Sefidbakht et al, 2021;Zhang et al, 2021). Because β-catenin plays an important role in the formation and metastasis of tumor formation, small molecule inhibitors that target β-catenin are being developed to suppress tumor progression (Wang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

β-catenin promotes resistance to trastuzumab in breast cance

Hao

Zheng

et al. 2023

Acta Biochim Pol

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More than 1 million women worldwide are diagnosed with breast cancer (BC) each year. This study aims to explore the molecular mechanisms of β-catenin affecting the trastuzumab tolerance in HER2-positive BC. β-catenin in BC and non-BC tissue samples were assessed by immunohistochemistry. β-catenin and HER2 were over-expressed and knockdown to evaluate their role in tumorigenicity and trastuzumab resistance in cell and animal models using soft-agar and xenograft assays. Confocal laser immunofluorescence assay and co-immunoprecipitation were used to assess protein-protein binding. Expression of genes was detected using Western blot analysis. β-catenin was highly expressed in primary and metastatic BC, overexpression of β-catenin increased the colony formation of MCF7 cells when it was co-expressed with HER2 and synergically increased the tumor size in immunodeficient mice. Overexpression of β-catenin also increased the phosphorylation of HER2 and HER3 and increased the size of tumor derived from HER2-elevated cells. Confocal laser immunofluorescence assay showed that β-catenin and HER2 were co-localized on the membrane of MDA-MB-231 cells, suggesting that β-catenin binds HER2 to activate the HER2 signaling pathway. Immunoprecipitation of β-catenin and HER2 also confirmed this binding. On the other hand, knockdown of β-catenin in MDA-MB-231 cell lines decreased the activity of SRC and decreased phosphorylation of HER2 at Y877 and Y1248. The interaction between HER2 and SRC was enhanced when β-catenin was overexpressed, and β-catenin increased the resistance of tumor derived from HER2 elevated BT474 cells to trastuzumab. Further analysis showed that trastuzumab inhibited the activation of HER3, but SRC was still highly expressed in cells overexpressing β-catenin. Our work demonstrates that β-catenin is highly expressed in BC and it synergically promotes formation and progress of BC with HER2. β-catenin binds with HER2 leading to enhanced interaction with SRC and resistance to trastuzumab.

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“…24,25 Aberrant activation of β-catenin has been observed in metastatic breast cancer and is associated with increased tumor aggressiveness and metastatic potential. 26,27 Although YAP and β-catenin both contribute to the cellular mechanotransduction, their interaction and synergistic effects in breast cancer metastasis remains unclear. It has been shown that YAP is a component of the β-catenin destruction complex, and YAP is sequestered in the cytoplasm to interact with the destruction complex.…”

mentioning

confidence: 99%

Deciphering the Mechanotransduction Symphony: Stiffness-Dependent Interplay of YAP and β-Catenin in Breast Cancer Metastasis

Geng,

Su,

et al. 2024

Preprint

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Metastatic breast cancer poses a formidable clinical challenge, demanding a comprehensive understanding of the intricate signaling networks orchestrating disease progression. Herein, our findings revealed a pronounced increase in the nuclear translocation of both YAP and β-catenin in MDA-MB-231 cells exposed to a stiff substrate (32 kPa). Intriguingly, YAP knockdown resulted in elevated β-catenin nuclear translocation on soft substrates (2 kPa), while no significant change was observed on stiff substrates. Concurrently, the expression of Wnt/β-catenin downstream genes ( CCND1 and AXIN2) and cell migration were downregulated in MDA-MB-231 cells on stiff substrates following YAP knockdown. Conversely, on soft substrates, β-catenin nuclear localization, downstream gene expression, and cell migration remained unaltered unless both YAP and β-catenin were concurrently silenced, highlighting the compensatory role of β-catenin in response to YAP depletion in the cellular context of mechanotransduction within metastatic breast cancer cells. Moreover, our investigation revealed the significant impact of myosin-II and cell confluency on the interplay between YAP and β-catenin. Thus, we elucidated a paradigm in which β-catenin assumes a compensatory role in response to YAP knockdown, particularly under distinct mechanical conditions. The interplay is finely tuned to the mechanical microenvironment, highlighting the mechanosensitivity of this compensatory mechanism.

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Determination of β-catenin Expression in Breast Cancer and Its Relationship with Clinicopathologic Parameters

Cited by 5 publications

References 14 publications

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

β-catenin promotes resistance to trastuzumab in breast cance

Deciphering the Mechanotransduction Symphony: Stiffness-Dependent Interplay of YAP and β-Catenin in Breast Cancer Metastasis

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