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Endocytic protein intersectin1-S shuttles into nucleus to suppress the DNA replication in breast cancer

Huikun Zhang1,2,3,4, Zhifang Guo1,2,3,4, Xiaoli Liu1,2,3,4

  • 1Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.

Cell Death & Disease
|October 9, 2021
PubMed

Insights

Intersectin1-S (ITSN1-S) is found in breast cancer cell nuclei, suppressing DNA replication and R-loop resolution. This discovery offers a novel prognostic factor for breast cancer precision medicine.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Breast cancer requires novel biomarkers for precision medicine.
  • Existing molecular biomarkers are insufficient for personalized treatment strategies.
  • Intersectin1 (ITSN1) emerged as a candidate target from mRNA microarray analysis.

Purpose of the Study:

  • To investigate the localization and function of intersectin1-S (ITSN1-S) in breast cancer cells.
  • To identify novel molecular mechanisms and potential prognostic factors in breast cancer.
  • To explore the role of ITSN1-S in DNA replication, cell migration, and invasion.

Main Methods:

  • Investigated ITSN1-S localization in breast cancer cell nuclei and cytoplasm.
  • Identified nuclear localization and export signals within ITSN1-S.
  • Utilized ITSN1 gene knockout cells and in vivo assays for validation.
  • Analyzed interactions between ITSN1-S domains and other proteins (NDH II, PI3KC2α).
  • Assessed impact on DNA replication, R-loop resolution, cell migration, and invasion.

Main Results:

  • ITSN1-S is present in both the cytoplasm and nucleus of breast cancer cells.
  • Nuclear ITSN1-S interacts with nuclear DNA helicase II (NDH II), suppressing DNA replication and R-loop resolution.
  • Cytoplasmic ITSN1-S interacts with PI3KC2α, inhibiting cell migration and invasion via the PI3KC2α-AKT pathway.
  • Results were validated in ITSN1 knockout cells and in vivo models.
  • Clinical data suggests combined cytoplasmic and nuclear ITSN1-S is a potential independent prognostic factor.

Conclusions:

  • ITSN1-S exhibits novel nuclear localization in breast cancer cells.
  • ITSN1-S plays a dual role in suppressing DNA replication and cell invasion.
  • ITSN1-S represents a promising novel prognostic biomarker for breast cancer.

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