2. Academic Validation
  3. The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer

The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer

  • Cancer Discov. 2020 Aug;10(8):1226-1239. doi: 10.1158/2159-8290.CD-19-1262.
Hui Liu 1,  Marcia N Paddock 2,  Haibin Wang 3,  Charles J Murphy 2 4,  Renee C Geck 5,  Adrija J Navarro 5,  Gerburg M Wulf 6,  Olivier Elemento 4,  Volker Haucke 3,  Lewis C Cantley 7,  Alex Toker 1 8
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
  • 3 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
  • 4 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York.
  • 5 Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 6 Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • 7 Meyer Cancer Center, Weill Cornell Medicine, New York, New York. atoker@bidmc.harvard.edu LCantley@med.cornell.edu hliu5@bidmc.harvard.edu.
  • 8 Ludwig Center at Harvard, Boston, Massachusetts.
PMID: 32513774 DOI: 10.1158/2159-8290.CD-19-1262
Abstract

Inactivation of the tumor suppressor lipid Phosphatase INPP4B is common in triple-negative breast Cancer (TNBC). We generated a genetically engineered TNBC mouse model deficient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for Akt and MEK gene signatures. Consequently, mice with INPP4B deficiency are more sensitive to PI3K or MEK inhibitors compared with WT mice. Mechanistically, we found that INPP4B deficiency increases PI(3,4)P2 levels in endocytic vesicles but not at the plasma membrane. Moreover, INPP4B loss delays degradation of EGFR and MET, while promoting recycling of Receptor Tyrosine Kinases (RTK), thus enhancing the duration and amplitude of signaling output upon growth factor stimulation. Therefore, INPP4B inactivation in TNBC promotes tumorigenesis by modulating RTK recycling and signaling duration. SIGNIFICANCE: Inactivation of the lipid Phosphatase INPP4B is frequent in TNBC. Using a genetically engineered mouse model, we show that INPP4B functions as a tumor suppressor in TNBC. INPP4B regulates RTK trafficking and degradation, such that loss of INPP4B prolongs both PI3K and ERK activation.This article is highlighted in the In This Issue feature, p. 1079.

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