Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells

Xu, Yingying; Yu, Hairu; Sun, Jiayi; Zhao, Zhao; Li, Shuang; Zhang, Xinfeng; Liao, Zhi-Xuan; Cui, Mingke; Li, Juan; Li, Chan; Zhang, Qiang

doi:10.4143/crt.2018.100

Cited by 22 publications

(12 citation statements)

References 31 publications

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“…PITX2 shows a strong correlation with specific drug responses (e.g., doxorubicin and letrozole) in preclinical cancer models mediated by ABC type drug transporters, importers, and other pathways [22-24], which supports the role of PITX2 as a drug-specific response marker. This is also supported by our results, showing a HR of 5.71 in the subgroup treated with anthracycline without taxanes, compared to a HR of 3.96 in the overall anthracycline-treated group (including or not including taxanes in the therapy regimen).…”

Section: Discussionmentioning

confidence: 85%

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

et al. 2020

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Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. Material and Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014). Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

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Section: Discussionmentioning

confidence: 85%

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

et al. 2020

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“…Recently, more and more studies show the critical role of PITX2 in many kinds of cancers. In breast cancer cells, upregulation of PITX2 promotes letrozole resistance via transcriptional activation of IFITM1 signaling [52]. The PITX2 DNA methylation was confirmed as a biomarker for the risk and prognosis of colorectal carcinoma [53], head and neck squamous cell carcinoma [54], urothelial bladder cancer [55] and prostate cancer [56].…”

Section: Discussionmentioning

confidence: 91%

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway

Luo

Yao

et al. 2019

Cancer Cell Int

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Background: The homeodomain transcription factor, PITX2 is associated with tumorigenesis of multiple cancers. In this research, we aimed to study the expression, function and mechanism of PITX2 in lung adenocarcinoma (LUAD). Methods: The TCGA dataset was used to analyze the expression and clinical significance of PITX2 in LUAD. The expression of PITX2 in tumor samples and LUAD cell lines was examined by quantitative real-time PCR (qRT-PCR) and western blotting. Small interfering RNAs (siRNAs) were constructed to knockdown PITX2 and to determine the physiological function of PITX2 in vitro. Xenograft model was used to confirm the role of PITX2 in vivo. Results: PITX2 was overexpressed in LUAD and patients with high level of PITX2 had a worse overall survival and an advanced clinical stage. Knockdown of PITX2 inhibited cell proliferation, migration and invasion of LUAD cells. Further study revealed that the oncogenic role of PITX2 was dependent on activating Wnt/β-catenin signaling pathway, especially by transcriptionally regulating the Wnt gene family member, WNT3A. Lastly, we identified miR-140-5p as a negative mediator of PITX2 by binding its 3′UTR and ectopic expression of miR-140-5p inhibited progression of LUAD cells via suppressing the expression of PITX2. Conclusions: Up-regulation of PITX2 acts as an oncogene in LUAD by activating Wnt/β-catenin signaling pathway, suggesting that PITX2 may serve as a novel diagnostic and prognostic biomarker in LUAD.

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“…It has been reported that PITX2 is involved in the development of several types of cancer [ 21 , 22 ]. A study demonstrated that the PITX2 upregulation could enhance the resistance of breast cancer cells to letrozole via activating the interferon‑induced transmembrane protein 1 pathway [ 23 ]. Another study revealed that microRNA-21 could enhanced the apoptosis and attenuate the proliferation of pituitary adenoma cells [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

The significance of homeodomain transcription factor 2 in colon cancer cells

Gong

Wang

et al. 2021

BioMed Eng OnLine

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Background Colon cancer is a serious malignant tumor. It has been reported that paired-like homeodomain transcription factor 2 (PITX2) can promote the progression of several types of cancer via regulating the Wnt/β-catenin pathway. It has also been demonstrated that high levels of long non-coding RNA (lncRNA) gastric carcinoma high expressed transcript 1 (GHET1) can also promote the development of cervical cancer via activating the Wnt/β-catenin pathway. However, whether PITX2 can affect the development of colon cancer via regulating the expression of lncRNA GHET1 remains unclear. Results The results demonstrated that PITX2 knockdown attenuated the proliferation, migration and invasion abilities of colon cancer cells. Additionally, PITX2 promoted the expression of lncRNA GHET1 via binding to its promoter. Overexpression of lncRNA GHET1 induced the expression of Wnt/β-catenin signaling-related proteins, cyclin D1, c-Myc and MMP-7. Furthermore, lncRNA GHET1 overexpression abrogated the PITX2 silencing-mediated decreased proliferation, migration and invasion abilities of colon cancer cells. Conclusion The findings of the present study suggested that PITX2 could enhance the proliferation, migration and invasion abilities of colon cancer cells via upregulating lncRNA GHET1 and activating the Wnt/β-catenin pathway.

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Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells

Cited by 22 publications

References 31 publications

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway

The significance of homeodomain transcription factor 2 in colon cancer cells

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