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Updated: Dec 19, 2025

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
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The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer

Hui Liu1, Marcia N Paddock2, Haibin Wang3

  • 1Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. atoker@bidmc.harvard.edu LCantley@med.cornell.edu hliu5@bidmc.harvard.edu.

Cancer Discovery
|June 10, 2020
PubMed

Insights

Loss of INPP4B, a tumor suppressor, promotes triple-negative breast cancer (TNBC) development. INPP4B deficiency enhances receptor tyrosine kinase signaling, increasing sensitivity to PI3K or MEK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Inactivation of the tumor suppressor lipid phosphatase INPP4B is frequently observed in triple-negative breast cancer (TNBC).
  • Understanding the role of INPP4B in TNBC pathogenesis is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the function of INPP4B as a tumor suppressor in TNBC.
  • To elucidate the molecular mechanisms by which INPP4B loss contributes to TNBC tumorigenesis.

Main Methods:

  • Generation of a genetically engineered TNBC mouse model deficient in INPP4B (knockout mice).
  • Comparative analysis of tumor incidence, gene expression signatures (AKT, MEK), and drug sensitivity between knockout and wild-type (WT) mice.
  • Investigation of phosphoinositide levels and receptor tyrosine kinase (RTK) trafficking and degradation pathways.

Main Results:

  • INPP4B knockout mice exhibited a dose-dependent increase in tumor incidence compared to WT mice.
  • Tumors from INPP4B-deficient mice showed enrichment for AKT and MEK gene signatures, correlating with increased sensitivity to PI3K or MEK inhibitors.
  • INPP4B deficiency led to increased PI(3,4)P2 levels in endocytic vesicles, delayed degradation of EGFR and MET, and promoted RTK recycling, enhancing signaling output.

Conclusions:

  • INPP4B acts as a tumor suppressor in TNBC by regulating RTK trafficking and degradation.
  • Loss of INPP4B prolongs PI3K and ERK activation, thereby promoting tumorigenesis in TNBC.
  • Targeting pathways modulated by INPP4B may offer therapeutic strategies for TNBC.

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