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Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.

التفاصيل البيبلوغرافية
العنوان: Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.
المؤلفون: Zhang KM; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Zhao DC; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Li ZY; BGI Research, Shenzhen, 518083, China.; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China., Wang Y; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Liu JN; Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shangdong, 264000, China., Du T; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Zhou L; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Chen YH; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Yu QC; BGI Research, Shenzhen, 518083, China.; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China., Chen QS; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Cai RZ; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Zhao ZX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Shan JL; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Hu BX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Zhang HL; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Feng GK; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Zhu XF; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Tang J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China., Deng R; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
المصدر: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Sep; Vol. 11 (35), pp. e2403592. Date of Electronic Publication: 2024 Jul 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Weinheim : WILEY-VCH, [2014]-
مواضيع طبية MeSH: Breast Neoplasms*/metabolism , Breast Neoplasms*/genetics , Breast Neoplasms*/drug therapy , Signal Transduction*/drug effects , Proto-Oncogene Proteins c-akt*/metabolism , Proto-Oncogene Proteins c-akt*/genetics , Nucleotidyltransferases*/metabolism , Nucleotidyltransferases*/genetics , Membrane Proteins*/metabolism , Membrane Proteins*/genetics , Drug Resistance, Neoplasm*/genetics, Humans ; Female ; Animals ; Mice ; Receptors, Estrogen/metabolism ; Receptors, Estrogen/genetics ; Feedback, Physiological ; Receptor, ErbB-2/metabolism ; Receptor, ErbB-2/genetics ; Cell Line, Tumor ; Disease Models, Animal
مستخلص: Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
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معلومات مُعتمدة: A2021073 Medical Scientific Foundation of Guangdong Province; 82373378 National Natural Science Foundation of China; 82173092 National Natural Science Foundation of China; 82372808 National Natural Science Foundation of China; 82103585 National Natural Science Foundation of China
فهرسة مساهمة: Keywords: AKT kinase; cGAS‐STING pathway; endocrine‐resistant breast cancer; positive feedback loop
المشرفين على المادة: EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
0 (STING1 protein, human)
EC 2.7.7.- (Nucleotidyltransferases)
0 (Membrane Proteins)
EC 2.7.7.- (cGAS protein, human)
0 (Receptors, Estrogen)
EC 2.7.10.1 (Receptor, ErbB-2)
EC 2.7.10.1 (ERBB2 protein, human)
تواريخ الأحداث: Date Created: 20240718 Date Completed: 20240926 Latest Revision: 20240928
رمز التحديث: 20240928
مُعرف محوري في PubMed: PMC11425221
DOI: 10.1002/advs.202403592
PMID: 39023171
قاعدة البيانات: MEDLINE
الوصف
تدمد:2198-3844
DOI:10.1002/advs.202403592