Cancer Research and Treatment

Original Articles

Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells: Ying-ying Xu, Hai-ru Yu, Jia-yi Sun, Zhao Zhao, Shuang Li, Xin-feng Zhang, Zhi-xuan Liao, Ming-ke Cui, Juan Li, Chan Li, Qiang Zhang; Cancer Res Treat. 2019;51(2):576-592. Published online July 18, 2018; DOI: https://doi.org/10.4143/crt.2018.100

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Purpose
Although the interferon α (IFNα) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa.
Materials and Methods
PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels.
Results
PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNα signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNα-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNα-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment.
Conclusion
These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa.

Citations

Citations to this article as recorded by

Proteomic profiling of ovarian clear cell carcinomas identifies prognostic biomarkers for chemotherapy
Liang Yue, Tingting Gong, Wenhao Jiang, Liujia Qian, Wangang Gong, Yaoting Sun, Xue Cai, Heli Xu, Fanghua Liu, He Wang, Sainan Li, Yi Zhu, Zhiguo Zheng, Qijun Wu, Tiannan Guo
PROTEOMICS.2024;[Epub] CrossRef
The role and mechanism of IFITM1 in developing acquired cisplatin resistance in small cell lung cancer
Xuemei Wang, Haihong Qian, Ling Yang, Shuangli Yan, Hua Wang, Xiu Li, Donghai Yang
Heliyon.2024; 10(10): e30806. CrossRef
PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis
Zhiliang Wang, Di Wu, Yue Zhang, Weibo Chen, Yang Yang, Yue Yang, Guangchen Zu, Yong An, Xianjun Yu, Yi Qin, Xiaowu Xu, Xuemin Chen
Experimental Cell Research.2024; 439(1): 114074. CrossRef
Chronic prostatitis/chronic pelvic pain syndrome impairs erectile function by inducing apoptosis in a rat model of experimental autoimmune prostatitis
Qi Gu, Jiaochen Luan, Mengchi Yu, Jiadong Xia, Zengjun Wang
International Journal of Impotence Research.2024;[Epub] CrossRef
Unveiling stem-like traits and chemoresistance mechanisms in ovarian cancer cells through the TGFβ1-PITX2A/B signaling axis
Sampurna Ghosh, Sk. Eashayan Tanbir, Tulika Mitra, Sib Sankar Roy
Biochemistry and Cell Biology.2024;[Epub] CrossRef
Oncogene‐mediated nuclear accumulation of lactate promotes epigenetic alterations to induce cancer cell proliferation
Shreya Bandopadhyay, Izaz M. Kamal, E. Padmanaban, Damayanti D. Ghosh, Saikat Chakrabarti, Sib S. Roy
Journal of Cellular Biochemistry.2023; 124(4): 495. CrossRef
Co-expression of DDR2 and IFITM1 promotes breast cancer cell proliferation, migration and invasion and inhibits apoptosis
Chenlu Wu, Jiafei Ying, Mei Dai, Jing Peng, Danhua Zhang
Journal of Cancer Research and Clinical Oncology.2022; 148(12): 3385. CrossRef
MiR-504-3p Has Tumor-Suppressing Activity and Decreases IFITM1 Expression in Non-Small Cell Lung Cancer Cells
Zining Liu, Weili Zhang, Biao Zhang, Shaomu Chen, Chunhua Ling
Genetic Testing and Molecular Biomarkers.2022; 26(7-8): 351. CrossRef
Disrupting interferon-alpha and NF-kappaB crosstalk suppresses IFITM1 expression attenuating triple-negative breast cancer progression
Olivia K. Provance, Eric S. Geanes, Asona J. Lui, Anuradha Roy, Sean M. Holloran, Sumedha Gunewardena, Christy R. Hagan, Scott Weir, Joan Lewis-Wambi
Cancer Letters.2021; 514: 12. CrossRef
The significance of homeodomain transcription factor 2 in colon cancer cells
Yang He, Peng Gong, Sitong Wang, Qing Xu, Jianhua Chen
BioMedical Engineering OnLine.2021;[Epub] CrossRef
Forkhead-box A3 (FOXA3) Represses Cancer Stemness and Partially Potentiates Chemosensitivity by Targeting Metastasis-Associated in Colon Cancer 1 (MACC1) Signaling Pathway in Colorectal Cancer Cells
Na Li, Yun Li, Hongbo Gao, Jing Li, Xiaoping Ma, Xiaomei Liu, Ping Gong, Xiaobin Cui, Yong Li
Current Cancer Drug Targets.2021; 21(3): 254. CrossRef
PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients
Rudolf Napieralski, Gabriele Schricker, Gert Auer, Michaela Aubele, Jonathan Perkins, Viktor Magdolen, Kurt Ulm, Moritz Hamann, Axel Walch, Wilko Weichert, Marion Kiechle, Olaf G. Wilhelm
Breast Care.2021; 16(5): 523. CrossRef
Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
Kebinuer Tuerxun, Shufang Zhang, Yuexin Zhang
Open Life Sciences.2021; 16(1): 1322. CrossRef
Deciphering the Roles of IFITM1 in Tumors
Renba Liang, Xinxiao Li, Xiaodong Zhu
Molecular Diagnosis & Therapy.2020; 24(4): 433. CrossRef
Interferon-induced transmembrane protein 1 (IFITM1) is essential for progression of laryngeal squamous cell carcinoma in an Osteopontin/NF-κB-dependent manner
Yong Yin, Keke Yang, Juanjuan Li, Peng Da, Zhenxin Zhang, Xiaoxia Qiu
Cancer Biomarkers.2020; 29(4): 521. CrossRef
DNA Methylation Events in Transcription Factors and Gene Expression Changes in Colon Cancer
Anna Díez-Villanueva, Rebeca Sanz-Pamplona, Robert Carreras-Torres, Ferran Moratalla-Navarro, M Henar Alonso, Laia Paré-Brunet, Susanna Aussó, Elisabet Guinó, Xavier Solé, David Cordero, Ramón Salazar, Maria Berdasco, Miguel A Peinado, Victor Moreno
Epigenomics.2020; 12(18): 1593. CrossRef
PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/β-catenin signaling pathway
Jing Luo, Yu Yao, Saiguang Ji, Qi Sun, Yang Xu, Kaichao Liu, Qiang Diao, Yong Qiang, Yi Shen
Cancer Cell International.2019;[Epub] CrossRef

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Circular RNA-ZFR Inhibited Cell Proliferation and Promoted Apoptosis in Gastric Cancer by Sponging miR-130a/miR-107 and Modulating PTEN: Tonglei Liu, Shuang Liu, Yu Xu, Ruo Shu, Feng Wang, Cheng Chen, Yujian Zeng, Huayou Luo; Cancer Res Treat. 2018;50(4):1396-1417. Published online January 24, 2018; DOI: https://doi.org/10.4143/crt.2017.537; Retraction in: Cancer Res Treat 2024;56(2):697

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Survival of Cancer Patients in Northeast China: Analysis of Sampled Cancers from Population-Based Cancer Registries: Yanxia Li, Liya Yu, Jun Na, Shuang Li, Li Liu, Huijuan Mu, Xuanjuan Bi, Xiaoxia An, Xun Li, Wen Dong, Guowei Pan; Cancer Res Treat. 2017;49(4):1106-1113. Published online February 2, 2017; DOI: https://doi.org/10.4143/crt.2016.613

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Purpose
The cancer survival was characterized by following up sampled subgroups of cancer cases from three population-based cancer registries in Northeast China.
Materials and Methods
Survival analysis was used to analyze 6,871 patients, who had one of the 21 most common cancers based on sampling from the population-based cancer registries of three cities in Liaoning Province. All patients were diagnosed between 2000 and 2002 and were followed up to the end of 2007 by active and passive methods. The 5-year age standardized relative survival rates (ASRS) were estimated for all cancers combined and each of the 21 individual cancers.
Results
The survival status was traced for 80.8% of 8,506 sampled cancer cases. The 5-year ASRS for all 21 cancers combined was 41.5% (95% confidence interval, 40.3 to 42.7), the highest ASRS was observed for thyroid cancer (85.2%), breast cancer (78.9%), uterine corpus cancer (75.9%), and urinary bladder cancer (70.2%); the lowest 5-year ASRS was noted in pancreatic cancer (8.8%), liver cancer (11.0%), esophageal cancer (18.8), and lung cancer (19.6%). The cancer survival rates in Liaoning cities were similar to those of urban areas in mainland China, but significantly lower than those in Hong Kong, Korea, and Japan.
Conclusion
The strikingly poor cancer survival rates in three cities of Liaoning Province and in other places in China highlight the need for urgent investment in cancer prevention, early detection, and standardized and centralized treatment.

Citations

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