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INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancerRodgers, Samuel J.; Ooms, Lisa M.; Oorschot, Viola M. J.; Schittenhelm, Ralf B.; Nguyen, Elizabeth V.; Hamila, Sabryn A.; Rynkiewicz, Natalie; Gurung, Rajendra; Eramo, Matthew J.; Sriratana, Absorn; Fedele, Clare G.; Caramia, Franco; Loi, Sherene; Kerr, Genevieve; Abud, Helen E.; Ramm, Georg; Papa, Antonella; Ellisdon, Andrew M.; Daly, Roger J.; McLean, Catriona A.; Mitchell, Christina A.
Nature communications, 05/2021, Letnik: 12, Številka: 1Journal Article
Abstract INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P 2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA -mutant ER + breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA -mutant ER + breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P 2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER + breast cancer via PI(3,4)P 2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
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