The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis.
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.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Lisa M
LM
Ooms
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Lauren C
LC
Binge
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Elizabeth M
EM
Davies
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Parvin
P
Rahman
Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Faculty of Medicine, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW 2010, Australia.
James R W
JR
Conway
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Rajendra
R
Gurung
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Daniel T
DT
Ferguson
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Antonella
A
Papa
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Clare G
CG
Fedele
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Jessica L
JL
Vieusseux
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Ryan C
RC
Chai
Ozgene Pty Ltd, Bentley DC, WA 6983, Australia.
Frank
F
Koentgen
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
John T
JT
Price
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
Tony
T
Tiganis
Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Faculty of Medicine, St Vincent's Clinical School, University of NSW, Darlinghurst, NSW 2010, Australia.
Paul
P
Timpson
Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC 3181, Australia.
Catriona A
CA
McLean
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: christina.mitchell@monash.edu.
Christina A
CA
Mitchell
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000072181:Inositol Polyphosphate 5-Phosphatases; D053208:Kaplan-Meier Estimate; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases