CTTN Overexpression Confers Cancer Stem Cell-like Properties and Trastuzumab Resistance via DKK-1/WNT Signaling in HER2 Positive Breast Cancer

Moon, Sojeong; Choi, Hyung Jun; Kye, Young-Hyeon; Jeong, Ga-Young; Kim, Hyung-Yong; Myung, Jaekyung

doi:10.3390/cancers15041168

Cited by 7 publications

(3 citation statements)

References 42 publications

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“…The absence of any association between cortactin expression and the prognosis of patients with breast cancer in these two studies is probably explained by the fact that the molecular subtypes of breast cancer were not separately analyzed in these studies. This assumption is supported by a recent study where cortactin overexpression in a HER2-type breast cancer was found to be associated with poor clinical outcome like other carcinomas [27]. Unlike the HER2-type breast cancer, cortactin protein expression in TNBC breast cancer is associated with good prognosis based on our data.…”

Section: Discussionsupporting

confidence: 91%

Effects of Cortactin Expression on Prognosis in Patients with Breast Cancer

Son,

Jee,

Cha

et al. 2023

Diagnostics

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Background: Cortactin is overexpressed in several types of invasive cancers. However, the role of cortactin expression in breast cancer prognosis has not been sufficiently elucidated. Therefore, we investigated the clinicopathological significance of cortactin in breast cancer. Methods: Tissue microarrays were prepared from a cohort of 506 patients with breast cancer, and cortactin expression was evaluated using immunohistochemistry. The cortactin immunoreactivity score (IRS) was quantified as the product of the intensity score and the percentage of immunoreactive cells. Cortactin expression was classified as low or high using the IRS (IRS ≤ 4 as a cortactin-low value and IRS > 4 as a cortactin-high value). We compared cortactin expression and clinicopathological factors according to the molecular subtypes of breast cancer. Results: Of 506 breast cancer cases, 333 and 173 showed high and low cortactin expression, respectively. Of the 333 patients with high cortactin expression, 204, 58, and 71 had luminal, HER2, and triple-negative breast cancer (TNBC), respectively. In the univariate and multivariate analyses of patients with TNBC, cortactin expression was found to be a significant prognostic factor for overall survival (OS). However, in all patients with non-TNBC, cortactin expression had no significant association with prognosis or overall survival. Survival curves revealed that among patients with TNBC, the high-cortactin group had a better prognosis in disease-free survival and OS. Conclusions: Cortactin expression may be a good biomarker for predicting the prognosis of patients with TNBC.

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Section: Discussionsupporting

confidence: 91%

Effects of Cortactin Expression on Prognosis in Patients with Breast Cancer

Son,

Jee,

Cha

et al. 2023

Diagnostics

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“…These results are promising as no validated biomarker, apart from HER2, can predict the benefit of the Tz approach, and thus guide individual therapeutic decisions [24]. Other authors have established a relation between cortactin and vinculin overexpression and cancer aggression and resistance, and have also proposed them as promising prognostic and predictive biomarkers [71][72][73]. These proteins could be related as a study linked them, wherein vinculin mediated the action of cortactin [74].…”

Section: Discussionmentioning

confidence: 99%

Potential Biomarkers Associated with Prognosis and Trastuzumab Response in HER2+ Breast Cancer

Castro-Guijarro,

Sanchez,

Flamini

2023

Cancers

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Breast cancer (BC) is the most common malignancy among women worldwide. Around 15–25% of BC overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with a worse prognosis and shortened disease-free survival. Therefore, anti-HER2 therapies have been developed, such as monoclonal antibodies (trastuzumab, Tz), antibody–drug conjugates (ado-trastuzumab emtansine, T-DM1), and pharmacological inhibitors of tyrosine kinase activity (lapatinib, Lp). Although Tz, the standard treatment, has significantly improved the prognosis of patients, resistance still affects a significant population of women and is currently a major challenge in clinical oncology. Therefore, this study aims to identify potential biomarkers to predict disease progression (prognostic markers) and the efficacy of Tz treatment (predictive markers) in patients with HER2+ BC. We hypothesize that proteins involved in cell motility are implicated in Tz-resistance. We aim to identify alterations in Tz-resistant cells to guide more efficient oncologic decisions. By bioinformatics, we selected candidate proteins and determined how their expression, localization, and the process they modulate were affected by anti-HER2 treatments. Next, using HER2+ BC patients’ data, we assessed these proteins as prognostic and predictive biomarkers. Finally, using Tz-resistant cells, we evaluated their roles in Tz response. We identified deregulated genes associated with cell motility in Tz/T-DM1-resistant vs. -sensitive cells. We showed that Tz, T-DM1, and Lp decrease cell viability, and their effect is enhanced in combinations. We determined synergism between Tz/T-DM1 and Lp, making possible a dose reduction of each drug to achieve the same therapeutic effect. We found that combinations (Tz/T-DM1 + Lp) efficiently inhibit cell adhesion and migration. Furthermore, we demonstrated the induction of FAK nuclear and cortactin peri-nuclear localization after T-DM1, Lp, and Tz/T-DM1 + Lp treatments. In parallel, we observed that combined treatments downregulate proteins essential for metastatic dissemination, such as SRC, FAK, and paxillin. We found that low vinculin (VCL) and cortactin (CTTN) mRNA expression predicts favorable survival rates and has diagnostic value to discriminate between Tz-sensible and Tz-resistant HER2+ BC patients. Finally, we confirmed that vinculin and cortactin are overexpressed in Tz-resistance cells, SKBR3-RTz. Moreover, we found that Tz plus FAK/paxillin/cortactin-silencing reduced cell adhesion/migration capacity in Tz-sensitive and -resistant cells. In conclusion, we demonstrate that combined therapies are encouraging since low doses of Tz/T-DM1 + Lp inhibit metastatic processes by downregulating critical protein expression and affecting its subcellular localization. We propose that vinculin and cortactin might contribute to Tz-sensibility/resistance in BC cells. Finally, we identify potential prognostic and predictive biomarkers that are promising for personalized BC management that would allow efficient patient selection in order to mitigate resistance and maximize the safety and efficacy of anti-HER2 therapies.

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“…The canonical Wnt protein activates transcription of β-catenin/T-cell factor (TCF)/lymphatic enhancing factor (LEF) target genes by transducing signaling β-catenin ( 23 , 24 ). Some researchers have demonstrated that Wnt antagonists with frequent genetic and epigenetic mutations in breast cancer led to β-catenin-mediated activation of Wnt target genes, suggesting that the Wnt-catenin-β1 (CTNNB1) signaling pathway plays an important role in the oncogenic process ( 25 , 26 ). Similarly, it has been reported in breast cancer that several cytosolic and nucleus components of the Wnt/β-catenin pathway is deregulated, such as DKK3, Dickkopf (DKK)-1, APC, Wnt inhibitor factor 1 (WIF1), SFRP5, MCC, glycogen synthase kinase-3β (GSK3B), and CTNNBIP1 ( 27 - 29 ).…”

Section: Introductionmentioning

confidence: 99%

Sinensetin suppresses breast cancer cell progression via Wnt/β-catenin pathway inhibition

Zhu,

Meng,

Wei

et al. 2024

Transl Cancer Res

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Background Although there are many treatments for breast cancer, such as surgery, radiotherapy, chemotherapy, estrogen receptor antagonists, immune checkpoint inhibitors and so on. However, safer and more effective therapeutic drugs for breast cancer are needed. Sinensetin, a safer therapeutic drugs, come from citrus species and medicinal plants used in traditional medicine, while its role and underlying mechanism in breast cancer remain unclear. Our study aimed to investigate the role and mechanism of sinensetin in breast cancer. Methods Cell Counting Kit-8 (CCK-8) was used to determine the safe concentration of sinensetin in MCF-10A, MCF7 and MDA-MB-231 cells; 120 μM sinensetin was used in subsequent experiments. Real time polymerase chain reaction (RT-PCR), Western blotting, Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay, Transwell invasion assay and Clone formation assay were used in this study to determine cell viability, mRNA expression, protein levels, apoptosis, proliferation, invasion and so on. Results Herein, our results showed that 120 μM sinensetin suppressed the cell viability and promoted apoptosis of MCF7 and MDA-MB-231 cells. Treatment with 120 µM sinensetin for 24 h showed no significant toxicity to normal mammary cells; 120 μM sinensetin decreased cell proliferation, invasion, and epithelial-mesenchymal transition (EMT), and downregulated β-catenin, lymphatic enhancing factor 1 (LEF1), T-cell factor (TCF) 1/TCF7, and TCF3/TCF7L1 expression in MCF7 and MDA-MB-231 cells. The Wnt agonist SKL2001 reversed the inhibitory effect of sinensetin on cell survival, metastasis, and EMT. Sinensetin-induced downregulation of β-catenin, LEF1, and TCF1/TCF7 expression were upregulated by SKL2001 in MCF7 and MDA-MB-231 cells. Conclusions In summary, sinensetin suppressed the metastasis of breast cancer cell via inhibition of Wnt/β-catenin pathway and there were no adverse effects on normal breast cells. Our study confirmed the role of sinensetin in breast cancer cells and provided a better understanding of the underlying mechanism.

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CTTN Overexpression Confers Cancer Stem Cell-like Properties and Trastuzumab Resistance via DKK-1/WNT Signaling in HER2 Positive Breast Cancer

Cited by 7 publications

References 42 publications

Effects of Cortactin Expression on Prognosis in Patients with Breast Cancer

Effects of Cortactin Expression on Prognosis in Patients with Breast Cancer

Potential Biomarkers Associated with Prognosis and Trastuzumab Response in HER2+ Breast Cancer

Sinensetin suppresses breast cancer cell progression via Wnt/β-catenin pathway inhibition

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