INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

Samuel J Rodgers; Lisa M Ooms; Viola M J Oorschot; Ralf B Schittenhelm; Elizabeth V Nguyen; Sabryn A Hamila; Natalie Rynkiewicz; Rajendra Gurung; Matthew J Eramo; Absorn Sriratana; Clare G Fedele; Franco Caramia; Sherene Loi; Genevieve Kerr; Helen E Abud; Georg Ramm; Antonella Papa; Andrew M Ellisdon; Roger J Daly; Catriona A McLean; Christina A Mitchell

doi:10.1038/s41467-021-23241-6

INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

Nat Commun. 2021 May 25;12(1):3140. doi: 10.1038/s41467-021-23241-6.

Authors

Samuel J Rodgers^{1

2}, Lisa M Ooms^{1

2}, Viola M J Oorschot^{3

4}, Ralf B Schittenhelm⁵, Elizabeth V Nguyen^{1

2}, Sabryn A Hamila^{1

2}, Natalie Rynkiewicz^{2

6}, Rajendra Gurung^{1

2}, Matthew J Eramo^{1

2}, Absorn Sriratana^{1

2}, Clare G Fedele^{2

7}, Franco Caramia⁷, Sherene Loi⁷, Genevieve Kerr^{8

9}, Helen E Abud^{8

9}, Georg Ramm^{1

2

3}, Antonella Papa^{1

2}, Andrew M Ellisdon^{1

2

10}, Roger J Daly^{1

2}, Catriona A McLean¹¹, Christina A Mitchell^{12

13}

Affiliations

¹ Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
² Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
³ Monash Ramaciotti Centre for Cryo Electron Microscopy, a Node of Microscopy Australia, Monash University, Victoria, Australia.
⁴ Electron Microscopy Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany.
⁵ Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
⁶ Babraham Institute, Cambridge, UK.
⁷ Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia.
⁸ Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁹ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
¹⁰ Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia.
¹¹ Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia.
¹² Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. [email protected].
¹³ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia. [email protected].

Abstract

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P₂ to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER⁺ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER⁺ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P₂ to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER⁺ breast cancer via PI(3,4)P₂ to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Breast / pathology
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / pathology*
Carcinogenesis / drug effects
Carcinogenesis / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases / genetics
Class I Phosphatidylinositol 3-Kinases / metabolism*
Endosomes / metabolism
Female
Gene Expression Profiling
Humans
Lysosomes / metabolism
Mice
Mutation
Phosphatidylinositol Phosphates / metabolism
Phosphoric Monoester Hydrolases / antagonists & inhibitors
Phosphoric Monoester Hydrolases / metabolism*
Proteolysis / drug effects
Proteomics
Thiazoles / pharmacology
Thiazoles / therapeutic use
Tissue Array Analysis
Wnt Signaling Pathway / drug effects
Xenograft Model Antitumor Assays
rab GTP-Binding Proteins / metabolism
rab7 GTP-Binding Proteins

Substances

Antineoplastic Agents
Phosphatidylinositol Phosphates
Thiazoles
phosphatidylinositol 3,4-diphosphate
phosphatidylinositol 3-phosphate
rab7 GTP-Binding Proteins
rab7 GTP-binding proteins, human
rab7 GTP-binding proteins, mouse
Alpelisib
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Phosphoric Monoester Hydrolases
phosphatidylinositol-3,4-bisphosphate 4-phosphatase
rab GTP-Binding Proteins