title: INPP4B and PTEN Loss Leads to PI-3,4-P2 Accumulation and Inhibition of PI3K in TNBC.
abstract: Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concerning whether PI-3,4-P2 contributes to Akt and downstream effector activation with the known canonical signaling second messenger, phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3). If PI-3,4-P2 is a positive effector, INPP4B would be a negative regulator of PI3K signaling, and there is some evidence to support this. Utilizing phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null triple-negative breast tumor cell lines, it was unexpectedly found that silencing INPP4B decreased basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitized cells to PI3K-α and PI3K-β isoform-specific inhibitors. Conversely, overexpression of INPP4B desensitized cells to PI3K inhibitors in a phosphatase activity-dependent manner. In summary, the current investigation of INPP4B in PTEN-null TNBC suggests new mechanistic insight and the potential for targeted therapy for this aggressive subset of breast cancer.Implications:These data support a model where PI-3,4-P2 is inhibitory toward PI3K, revealing a novel feedback mechanism under conditions of excessive signaling, and potentially an indication for PI3K-β isoform-specific inhibitors in PTEN-null TNBC that have lost INPP4B expression.Mol Cancer Res; 15(6); 765-75. ©2017 AACR.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California.|Howard Hughes Medical Institute, University of California, San Francisco, California.
authors.forename: Darien E
authors.initials: DE
authors.lastname: Reed
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California. kevan.shokat@ucsf.edu.|Howard Hughes Medical Institute, University of California, San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C060980:phosphatidylinositol 3,4-diphosphate; C055525:phosphatidylinositol 3-phosphate; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; C494929:PTEN protein, human