Specific roles of HSP27 S15 phosphorylation augmenting the nuclear function of HER2 to promote trastuzumab resistance

Soo Yeon Hwang, Seul Ki Choi, Seung Hee Seo, Hyunji Jo, Jae Ho Shin, Younghwa Na, Yun Sil Lee, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.

Original languageEnglish
Article number1540
Pages (from-to)1-24
Number of pages24
JournalCancers
Volume12
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Breast cancer
  • Heat shock protein 27
  • Human epidermal growth factor receptor 2
  • Protein-protein interaction
  • Trastuzumab resistance

Fingerprint

Dive into the research topics of 'Specific roles of HSP27 S15 phosphorylation augmenting the nuclear function of HER2 to promote trastuzumab resistance'. Together they form a unique fingerprint.

Cite this