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EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties
Journal article   Open access   Peer reviewed

EPHA5 mediates trastuzumab resistance in HER2-positive breast cancers through regulating cancer stem cell-like properties

Yongfei Li, Jiahui Chu, Wanting Feng, Mengzhu Yang, Yanhong Zhang, Yanqiu Zhang, Ye Qin, Juan Xu, Jun Li, Shauna N Vasilatos, …
The FASEB journal, Vol.33(4), pp.4851-4865
04/2019
DOI: 10.1096/fj.201701561RRRR
PMID: 30620624
url
https://doi.org/10.1096/fj.201701561RRRRView
Published (Version of record) Open Access

Abstract

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 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.
 AC133 Antigen - metabolism Animals Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Drug Resistance, Neoplasm - genetics Female Gene Expression Regulation, Neoplastic - genetics Humans Mice Mice, Nude Middle Aged Nanog Homeobox Protein - metabolism Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Receptor, EphA5 - genetics Receptor, EphA5 - metabolism Receptor, ErbB-2 - metabolism Signal Transduction - drug effects Signal Transduction - genetics Trastuzumab - pharmacology Trastuzumab - therapeutic use

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