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ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to

Iris Tanaka1,2,3, Alina Chakraborty1,2,3, Olivier Saulnier4

  • 1Institut Curie, PSL Research University, CNRS UMR 3348, F-91405 Orsay, France.

Nucleic Acids Research
|January 17, 2020
PubMed

Insights

Alternative splicing (AS) programs regulated by ZRANB2 and SYF2 contribute to breast cancer cell resistance to doxorubicin chemotherapy. Targeting the ECT2-Ex5+ splice variant may overcome this resistance, improving patient prognosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Alternative splicing (AS) regulatory pathways in anticancer drug resistance remain largely unexplored.
  • Doxorubicin is a key chemotherapeutic agent for breast cancer, but resistance limits its efficacy.

Purpose of the Study:

  • To investigate AS programs and splicing factors involved in acquired doxorubicin resistance in breast cancer.
  • To identify novel therapeutic targets for overcoming doxorubicin resistance.

Main Methods:

  • RNA interference (RNAi) screen of splicing factors in a doxorubicin-resistant breast cancer cell model.
  • RNA sequencing (RNA-seq) to analyze AS events and gene expression.
  • In vivo mouse xenograft models to assess therapeutic efficacy.

Main Results:

  • 1723 AS events and 41 splicing factors were regulated in doxorubicin-resistant cells.
  • Depletion of ZRANB2 and SYF2 partially reversed doxorubicin resistance by modulating AS programs.
  • These programs converged on the ECT2-Ex5+ splice variant, which was crucial for resistance and S-phase accumulation.
  • Inhibition of ECT2-Ex5+ inclusion reduced tumor growth in vivo and correlated with poor prognosis in patients.

Conclusions:

  • ZRANB2 and SYF2 control AS programs that promote breast cancer cell resistance to doxorubicin.
  • The ECT2-Ex5+ splice variant is a key mediator of this resistance.
  • Targeting ZRANB2, SYF2, or ECT2-Ex5+ represents a potential strategy to enhance chemotherapy effectiveness.

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