EGFR-independent Elk1/CIP2A signalling mediates apoptotic effect of an erlotinib derivative TD52 in triple-negative breast cancer cells

Chun Yu Liu, Tzu Ting Huang, Chun Teng Huang, Ming Hung Hu, Duen Shian Wang, Wan Lun Wang, Wen Chun Tsai, Chia Han Lee, Ka Yi Lau, Hsiu Ping Yang, Ming Huang Chen, Chung Wai Shiau, Ling Ming Tseng, Kuen Feng Chen

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Objectives Cancerous inhibitor of protein phosphatase 2A (CIP2A) has emerged as a therapeutic determinant mediating the anti-cancer effects of several new agents. We investigated the efficacy and mechanism of TD52, an erlotinib derivative with minimal p-EGFR inhibition but significant CIP2A downregulation, in triple-negative breast cancer (TNBC) cells. Methods TNBC lines were used for in vitro studies. Cell apoptosis was examined by flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western blot. In vivo efficacy of TD52 was tested in xenograft nude mice. Results We explored the CIP2A mRNA expression in a publically available database and found that higher levels of CIP2A mRNA is associated with worse recurrence-free survival in patients with TNBC. TD52-enhanced apoptosis accompanied with CIP2A downregulation and CIP2A overexpression protected cells from TD52-mediated apoptosis. The activity of protein phosphatase 2A (PP2A) was also increased in TD52-treated cells. TD52-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, TD52 indirectly downregulated CIP2A transcription via disturbing the binding of Elk1 to the CIP2A promoter. Importantly, TD52 showed anti-tumour activity in mice bearing TNBC xenograft tumours and downregulated CIP2A and p-Akt in these xenografted tumours. Interestingly, higher Elk1 mRNA expression was also associated with worse recurrence-free survival in TNBC patients by Kaplan–Meier survival analysis. Conclusion Our findings indicated that EGFR-independent pharmacological modulation on Elk1/CIP2A signalling mediates the apoptotic effect of TD52 in TNBC cells, suggesting the potential therapeutic strategy.

Original languageEnglish
Pages (from-to)112-123
Number of pages12
JournalEuropean Journal of Cancer
Volume72
DOIs
Publication statusPublished - Feb 1 2017
Externally publishedYes

Keywords

  • CIP2A
  • EGFR
  • Elk1
  • Erlotinib
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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