The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

Lisa M Ooms; Lauren C Binge; Elizabeth M Davies; Parvin Rahman; James R W Conway; Rajendra Gurung; Daniel T Ferguson; Antonella Papa; Clare G Fedele; Jessica L Vieusseux; Ryan C Chai; Frank Koentgen; John T Price; Tony Tiganis; Paul Timpson; Catriona A McLean; Christina A Mitchell

doi:10.1016/j.ccell.2015.07.003

The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis

Cancer Cell. 2015 Aug 10;28(2):155-69. doi: 10.1016/j.ccell.2015.07.003.

Authors

Lisa M Ooms¹, Lauren C Binge¹, Elizabeth M Davies¹, Parvin Rahman¹, James R W Conway², Rajendra Gurung¹, Daniel T Ferguson¹, Antonella Papa¹, Clare G Fedele¹, Jessica L Vieusseux¹, Ryan C Chai¹, Frank Koentgen³, John T Price¹, Tony Tiganis¹, Paul Timpson², Catriona A McLean⁴, Christina A Mitchell⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
² Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Faculty of Medicine, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW 2010, Australia.
³ Ozgene Pty Ltd, Bentley DC, WA 6983, Australia.
⁴ Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC 3181, Australia.
⁵ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: christina.mitchell@monash.edu.

PMID: 26267533
DOI: 10.1016/j.ccell.2015.07.003

Abstract

Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer.

Publication types

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

MeSH terms

Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics*
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Inositol Polyphosphate 5-Phosphatases
Kaplan-Meier Estimate
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Neoplasm Metastasis
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphoric Monoester Hydrolases / genetics*
Phosphoric Monoester Hydrolases / metabolism
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Tumor Burden / genetics
Xenograft Model Antitumor Assays / methods

Substances

Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Phosphoric Monoester Hydrolases
Inositol Polyphosphate 5-Phosphatases