FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer

Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max A. K. Rätze, Manuel Saornil, Lilian M. Sluimer, Rutger C. C. Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn M. T. Burgering, Hendrika M. Oosterkamp, Susanne M. A. Lens, Judith Klumperman, Sabine C. Linn, Patrick W. B. Derksen

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.
Original languageEnglish
Article number110584
JournalCell reports
Volume39
Issue number1
DOIs
Publication statusPublished - 5 Apr 2022

Keywords

  • DCNT2
  • FER
  • analog sensitive
  • breast cancer
  • dynactin
  • dynamitin
  • endosomal recycling
  • metastasis
  • taxanes

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