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BRCA1/p220 loss triggers BRCA1-IRIS overexpression via mRNA stabilization in breast cancer cells

Yoshiko Shimizu1, Nicole Mullins, Zannel Blanchard

  • 1Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.

Oncotarget
|March 21, 2012
PubMed

Insights

Loss of BRCA1/p220 expression in breast cancer cells leads to BRCA1-IRIS overexpression, promoting aggressive triple-negative/basal-like tumor growth and survival. Restoring BRCA1/p220 reduces these effects and induces cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Triple-negative/basal-like (TN/BL) breast cancers are aggressive and linked to low BRCA1/p220 expression.
  • BRCA1/p220 loss is a key feature of these difficult-to-treat tumors.

Purpose of the Study:

  • To investigate the post-transcriptional mechanism linking BRCA1/p220 loss to TN/BL breast cancer.
  • To explore the role of BRCA1-IRIS in the development of aggressive breast cancer phenotypes.

Main Methods:

  • Silencing BRCA1/p220 in normal human mammary epithelial (HME) cells.
  • Analyzing the expression of RNA-destabilizing proteins (AUF1, pCBP2) and BRCA1-IRIS mRNA.
  • Overexpressing BRCA1-IRIS in HME cells and observing TN/BL marker expression.
  • Silencing BRCA1-IRIS or restoring BRCA1/p220 in TN/BL cell lines (SUM149, HCC1937).

Main Results:

  • BRCA1/p220 silencing reduced AUF1 and pCBP2, which destabilize BRCA1-IRIS mRNA.
  • BRCA1-IRIS overexpression in HME cells induced TN/BL markers (cytokeratins 5/17, p-cadherin, EGFR, cyclin E) and pro-survival proteins (AKT, survivin).
  • BRCA1-IRIS silencing or BRCA1/p220 restoration in TN/BL cells decreased TN/BL markers, AKT, survivin, and induced cell death.

Conclusions:

  • BRCA1/p220 loss triggers BRCA1-IRIS overexpression via a post-transcriptional mechanism.
  • BRCA1-IRIS overexpression drives aggressive TN/BL breast cancer by upregulating TN/BL and survival markers.
  • Targeting BRCA1-IRIS or restoring BRCA1/p220 may offer therapeutic strategies for aggressive breast cancers.

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