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.
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