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.
Copyright © 2015 Elsevier Inc. All rights reserved.
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