Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy
| العنوان: | Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy |
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| المؤلفون: | Sabrina Herrera, Meghana V. Trivedi, Sufeng Mao, Mario Giuliano, Joe W. Gray, Carmine De Angelis, Sara López-Tarruella, Huizhong Hu, Laura M. Heiser, Yen-Chao Wang, C. Kent Osborne, Rachel Schiff, Nicholas J. Wang, Mothaffar F. Rimawi, Anne Pavlick, Agostina Nardone, Jenny C. Chang, Alejandro Contreras, Susan G. Hilsenbeck, Gary C. Chamness, Xiaoyong Fu, Tao Wang, Carolina Gutierrez |
| المساهمون: | Giuliano, Mario, Hu, H, Wang, Yc, Fu, X, Nardone, Agostina, Herrera, S, Mao, S, Contreras, A, Gutierrez, C, Wang, T, Hilsenbeck, Sg, DE ANGELIS, Carmine, Wang, Nj, Heiser, Lm, Gray, Jw, Lopez Tarruella, S, Pavlick, Ac, Trivedi, Mv, Chamness, Gc, Chang, Jc, Osborne, Ck, Rimawi, Mf, Schiff, R. |
| المصدر: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| بيانات النشر: | American Association for Cancer Research (AACR), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, medicine.medical_specialty, Time Factors, Antineoplastic Agents, Hormonal, Cell Survival, Receptor, ErbB-2, medicine.medical_treatment, Gene Expression, Estrogen receptor, Breast Neoplasms, Lapatinib, Article, Mice, Downregulation and upregulation, Cell Line, Tumor, Internal medicine, Animals, Humans, Medicine, Molecular Targeted Therapy, Epidermal growth factor receptor, skin and connective tissue diseases, neoplasms, Neoadjuvant therapy, biology, Fulvestrant, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Neoadjuvant Therapy, Disease Models, Animal, Endocrinology, Proto-Oncogene Proteins c-bcl-2, Receptors, Estrogen, Oncology, Drug Resistance, Neoplasm, Tumor progression, Quinazolines, Cancer research, biology.protein, Female, Receptors, Progesterone, business, Biomarkers, Signal Transduction, medicine.drug |
| الوصف: | Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti–HER2-resistant growth (P < 0.0001). Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. Clin Cancer Res; 21(17); 3995–4003. ©2015 AACR. |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f4b1598f486d1beb5e4551a1d1f12f3dTest https://doi.org/10.1158/1078-0432.ccr-14-2728Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f4b1598f486d1beb5e4551a1d1f12f3d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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