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The C-terminal putative nuclear localization sequence of breast cancer metastasis suppressor 1, BRMS1, is necessary

Douglas R Hurst1, Yi Xie, John W Thomas

  • 1Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA. DHurst@uab.edu

Plos One
|February 8, 2013
PubMed

Insights

Breast cancer metastasis suppressor 1 (BRMS1) protein

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Breast cancer metastasis suppressor 1 (BRMS1) is a protein that inhibits metastasis in various cancer cells.
  • BRMS1 primarily functions in the nucleus, interacting with chromatin remodeling complexes.
  • Recent findings suggest BRMS1 may also have cytoplasmic functions.

Purpose of the Study:

  • To investigate the role of nuclear localization sequences (NLS) in BRMS1-mediated metastasis suppression.
  • To determine if cytoplasmic localization of BRMS1 affects its metastasis-suppressing activity.

Main Methods:

  • Mutagenesis of BRMS1 to alter its nuclear localization sequences (NLS1 and NLS2).
  • Transduction of MDA-MB-231 breast cancer cells with modified BRMS1 variants.
  • Evaluation of metastasis suppression in a mouse xenograft model.
  • Co-immunoprecipitation assays to assess protein interactions.
  • Analysis of microRNA expression (miR-10b).

Main Results:

  • BRMS1 variants with altered NLS showed varying degrees of nuclear and cytoplasmic localization.
  • BRMS1(NLS2,2), which localizes predominantly to the cytoplasm, suppressed metastasis by 85%.
  • BRMS1(NLS2,2) maintained interaction with SIN3A in both nucleus and cytoplasm and downregulated miR-10b.
  • BRMS1 variants primarily localized in the nucleus did not significantly suppress metastasis.

Conclusions:

  • Nuclear localization sequence 2 (NLS2) plays a critical role in cytoplasmic localization and metastasis suppression, independent of nuclear import.
  • Cytoplasmic function of BRMS1, mediated by NLS2, is crucial for inhibiting breast cancer metastasis.
  • BRMS1's metastasis-suppressing activity involves regulating pro-metastatic microRNAs like miR-10b.

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