Cancer Research and Treatment

Original Articles

Breast cancer

The Association of Estrogen Receptor Activity, Interferon Signaling, and MHC Class I Expression in Breast Cancer: In Hye Song, Young-Ae Kim, Sun-Hee Heo, Won Seon Bang, Hye Seon Park, Yeon ho Choi, Heejae Lee, Jeong-Han Seo, Youngjin Cho, Sung Wook Jung, Hee Jeong Kim, Sei Hyun Ahn, Hee Jin Lee, Gyungyub Gong; Cancer Res Treat. 2022;54(4):1111-1120. Published online December 21, 2021; DOI: https://doi.org/10.4143/crt.2021.1017

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Purpose
The expression of major histocompatibility complex class I (MHC I) has previously been reported to be negatively associated with estrogen receptor (ER) expression. Furthermore, MHC I expression, level of tumor-infiltrating lymphocytes (TILs), and expression of interferon (IFN) mediator MxA are positively associated with one another in human breast cancers. This study aimed to investigate the mechanisms of association of MHC I with ER and IFN signaling.
Materials and Methods
The human leukocyte antigen (HLA)-ABC protein expression was analyzed in breast cancer cell lines. The expressions of HLA-A and MxA mRNAs were analyzed in MCF-7 cells in Gene Expression Omnibus (GEO) data. ER and HLA-ABC expressions, Ki-67 labeling index and TIL levels in tumor tissue were also analyzed in ER+/ human epidermal growth factor receptor 2 (HER2)- breast cancer patients who randomly received either neoadjuvant chemotherapy or estrogen modulator treatment followed by resection.
Results
HLA-ABC protein expression was decreased after β-estradiol treatment or hESR-GFP transfection and increased after fulvestrant or IFN-γ treatment in cell lines. In GEO data, HLA-A and MxA expression was increased after ESR1 shRNA transfection. In patients, ER Allred score was significantly lower and the HLA-ABC expression, TIL levels, and Ki-67 were significantly higher in the estrogen modulator treated group than the chemotherapy treated group.
Conclusion
MHC I expression and TIL levels might be affected by ER pathway modulation and IFN treatment. Further studies elucidating the mechanism of MHC I regulation could suggest a way to boost TIL influx in cancer in a clinical setting.

Citations

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Estrogen receptor regulation of the immune microenvironment in breast cancer
Conor McGuinness, Kara L. Britt
The Journal of Steroid Biochemistry and Molecular Biology.2024; 240: 106517. CrossRef
Bioinformatic-Experimental Screening Uncovers Multiple Targets for Increase of MHC-I Expression through Activating the Interferon Response in Breast Cancer
Xin Li, Zilun Ruan, Shuzhen Yang, Qing Yang, Jinpeng Li, Mingming Hu
International Journal of Molecular Sciences.2024; 25(19): 10546. CrossRef
Hormone Receptor Signaling and Breast Cancer Resistance to Anti-Tumor Immunity
Alexandra Moisand, Mathilde Madéry, Thomas Boyer, Charlotte Domblides, Céline Blaye, Nicolas Larmonier
International Journal of Molecular Sciences.2023; 24(20): 15048. CrossRef

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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

Abstract PDF Supplementary Material PubReader ePub

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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21 Web of Science
17 Crossref

Expression of Immunoproteasome Subunit LMP7 in Breast Cancer and Its Association with Immune-Related Markers: Miseon Lee, In Hye Song, Sun-Hee Heo, Young-Ae Kim, In Ah Park, Won Seon Bang, Hye Seon Park, Gyungyub Gong, Hee Jin Lee; Cancer Res Treat. 2019;51(1):80-89. Published online February 26, 2018; DOI: https://doi.org/10.4143/crt.2017.500

Abstract PDF PubReader ePub

Purpose
In the presence of interferon, proteasome subunits are replaced by their inducible counterparts to form an immunoproteasome (IP) plays a key role in generation of antigenic peptides presented by MHC class I molecules, leading to elicitation of a T cell‒mediated immune response. Although the roles of IP in other cancers, and inflammatory diseases have been extensively studied, its significance in breast cancer is unclear.
Materials and Methods
We investigated the expression of LMP7, an IP subunit, and its relationship with immune system components in two breast cancer cohorts.
Results
In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress-associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]). Patients with higher LMP7 expression had better disease-free survival outcomes than those with no or low expression in the positive lymph node metastasis group (p=0.041).
Conclusion
Close association between the TIL levels and LMP7 expression in breast cancer indicates that better antigen presentation through greater LMP7 expression might be associated with more TILs.

Citations

Citations to this article as recorded by

Multikinase inhibitors modulate non-constitutive proteasome expression in colorectal cancer cells
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314 Download
24 Web of Science
26 Crossref

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