| Autor: |
Li Y; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and.; Department of Breast Diseases, Jiangsu Province Hospital of Traditional Chinese Medicine (TMC)/Affiliated Hospital of Nanjing University of TCM, Nanjing, China., Chu J; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Feng W; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Yang M; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Zhang Y; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Zhang Y; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Qin Y; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and., Xu J; Nanjing Maternal and Child Health Medical Institute, Affiliated Obstetrics and Gynecology Hospital, Nanjing Medical University, Nanjing, China., Li J; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Vasilatos SN; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and., Fu Z; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Nanjing Maternal and Child Health Medical Institute, Affiliated Obstetrics and Gynecology Hospital, Nanjing Medical University, Nanjing, China., Huang Y; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and., Yin Y; Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. |
| Abstrakt: |
Trastuzumab is a successful, rationally designed therapy that provides significant clinical benefit for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients. However, about half of individuals with HER2-positive breast cancer do not respond to trastuzumab treatment because of various resistance mechanisms, including but not limited to: 1) shedding of the HER2 extracellular domain, 2) steric hindrance ( e.g., MUC4 and MUC1), 3) parallel pathway activation (this is the general mechanism cited in the quote above), 4) perturbation of downstream signaling events ( e.g., PTEN loss or PIK3CA mutation), and 5) immunologic mechanisms (such as FcR polymorphisms). EPHA5, a receptor tyrosine kinase, has been demonstrated to act as an anticancer agent in several cancer cell types. In this study, deletion of EPHA5 can significantly increase the resistance of HER2-positive breast cancer patients to trastuzumab. To investigate how EPHA5 deficiency induces trastuzumab resistance, clustered regularly interspaced short palindromic repeat technology was used to create EPHA5-deficient variants of breast cancer cells. EPHA5 deficiency effectively increases breast cancer stem cell (BCSC)-like properties, including NANOG, CD133+, E-cadherin expression, and the CD44 + /CD24 -/low phenotype, concomitantly enhancing mammosphere-forming ability. EPHA5 deficiency also caused significant aggrandized tumor malignancy in trastuzumab-sensitive xenografts, coinciding with the up-regulation of BCSC-related markers and intracellular Notch1 and PTEN/AKT signaling pathway activation. These findings highlight that EPHA5 is a potential prognostic marker for the activity of Notch1 and better sensitivity to trastuzumab in HER2-positive breast cancer. Moreover, patients with HER2-positive breast cancers expressing high Notch1 activation and low EPHA5 expression could be the best candidates for anti-Notch1 therapy.-Li, Y., Chu, J., Feng, W., Yang, M., Zhang, Y., Zhang, Y., Qin, Y., Xu, J., Li, J., Vasilatos, S. N., Fu, Z., Huang, Y., Yin, Y. EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties. |
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