INPP4B Suppresses HER2-induced Mesenchymal Transition in HER2+ Breast Cancer and Enhances Sensitivity to Lapatinib.

Human epidermal growth factor receptor 2 positive (HER2 + ) breast cancer (BC) tends to metastasize and has a bad prognosis due to its high malignancy and rapid progression. Inositol polyphosphate 4-phosphatase isoenzymes type II (INPP4B) plays unequal roles in the development of various cancer. However, the function of INPP4B in HER2 + BC has not been elucidated. Here we found that INPP4B expression was significantly lower in HER2 + BC and positively correlated with the prognosis by bioinformatics and tissue immunofluorescence analyses. Overexpression of INPP4B inhibited cell proliferation, migration, and growth of xenografts in HER2 + BC cells. Conversely, depletion of INPP4B reversed these effects and activated the PDK1/AKT and Wnt/β-catenin signaling pathways to promote epithelial-mesenchymal transition (EMT) progression. Moreover, INPP4B overexpression blocked epidermal growth factor (EGF) −induced cell proliferation, migration and EMT progression, whereas INPP4B depletion antagonized HER2 depletion in reduction of cell proliferation and migration of HER2 + BC cells. Additionally, Lapatinib (LAP) inhibited HER2 + BC cell survival, proliferation and migration, and its effect was further enhanced by overexpression of INPP4B. In summary, our results illustrate that INPP4B suppresses HER2 + BC growth, migration and EMT, and its expression level affects patient outcome, further providing new insights into clinical practice.