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

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2015

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

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

LM Ooms;LC Binge;EM Davies;P Rahman;JR Conway;R Gurung;DT Ferguson;A Papa;CG Fedele;JL Vieusseux;RC Chai;F Koentgen;JT Price;T Tiganis;P Timpson;CA McLean;CA Mitchell

Monash University, Clayton, VIC, Australia; The Kinghorn Cancer Centre and University of NSW, Darlinghurst, Australia; Ozgene Pty Ltd, Bentley, WA, Australia; Alfred Hospital, Prahran, VIC, Australia.

Service type: Knockout mice

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.

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