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SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer

Jessica A Gasser1, Hiroyuki Inuzuka1, Alan W Lau1

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Molecular Cell
|December 3, 2014
PubMed

Insights

Breast cancer PIK3CA mutations activate SGK3 signaling, independent of Akt. This pathway, involving INPP4B, drives tumor growth and metastasis, highlighting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Oncogenic mutations in PIK3CA are common in breast cancer.
  • The PI3K/Akt pathway is a key driver, but Akt-independent PI3K signaling is not well understood.

Purpose of the Study:

  • Investigate mechanisms of PI3K-mediated tumorigenesis beyond Akt.
  • Identify novel PI3K effectors and their roles in breast cancer progression.

Main Methods:

  • Analysis of gene amplification and protein activation in breast cancer samples.
  • In vitro and in vivo studies of SGK3, INPP4B, and NDRG1 function.
  • Investigated downstream targets and signaling pathways.

Main Results:

  • SGK3 is amplified and activated downstream of PIK3CA, dependent on INPP4B.
  • INPP4B enhances SGK3 activation while suppressing Akt phosphorylation.
  • Activated SGK3 promotes 3D proliferation, invasion, and tumorigenesis by degrading NDRG1.

Conclusions:

  • PIK3CA-mutated breast cancers can activate SGK3 signaling while suppressing Akt.
  • INPP4B and SGK3 play oncogenic roles in these tumors.
  • This study reveals a novel PI3K-INPP4B-SGK3 signaling axis in breast cancer progression.

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