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Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression

Binbin Guo1, Siqi Wu1, Xun Zhu2

  • 1Department of Genetics, Medical College of Soochow University, Suzhou, China.

The EMBO Journal
|November 23, 2019
PubMed

Insights

Transforming growth factor-beta (TGF-β) regulates breast cancer metastasis through translational control of the micropeptide CIP2A-BP. Lower CIP2A-BP levels predict poor survival, but its restoration inhibits metastasis and improves outcomes in models.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Translational Medicine

Background:

  • Transforming growth factor-beta (TGF-β) signaling is crucial for breast cancer metastasis.
  • TGF-β influences tumor progression via both transcriptional and translational regulation.
  • Micropeptides encoded by long non-coding RNAs are emerging as key regulators in cancer.

Purpose of the Study:

  • To identify and characterize novel micropeptides regulated by TGF-β in breast cancer.
  • To elucidate the mechanism by which TGF-β controls the translation of the micropeptide CIP2A-BP.
  • To evaluate the prognostic and therapeutic potential of CIP2A-BP in triple-negative breast cancer (TNBC).

Main Methods:

  • Bioinformatic analysis and experimental validation in breast cancer cell lines (including TNBC).
  • Investigation of TGF-β/Smad signaling pathway and its effect on translation initiation factors (4E-BP1, eIF4E).
  • In vivo studies using the MMTV-PyMT mouse model and direct micropeptide administration.

Main Results:

  • TGF-β downregulates the translation of micropeptide CIP2A-BP from LINC00665 via the 4E-BP1/eIF4E axis.
  • CIP2A-BP inhibits the PI3K/AKT/NFκB pathway by modulating PP2A activity, reducing metastasis-associated factors (MMP-2, MMP-9, Snail).
  • Reduced CIP2A-BP expression correlates with TNBC metastasis and poor survival; its introduction curtails metastasis and improves survival in preclinical models.

Conclusions:

  • CIP2A-BP is a novel TGF-β-regulated micropeptide with a critical role in suppressing breast cancer metastasis.
  • CIP2A-BP serves as a prognostic biomarker for TNBC.
  • CIP2A-BP represents a promising therapeutic target for TNBC treatment.
Keywords:
TNBCCIP2A-BPPI3K/AKT/NFκB pathwaysinvasion and metastasis

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