INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer.

Nature communications 2021 May 25

filter terms:

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 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)P2 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)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

Citation

Samuel J Rodgers, Lisa M Ooms, Viola M J Oorschot, Ralf B Schittenhelm, Elizabeth V Nguyen, Sabryn A Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J Eramo, Absorn Sriratana, Clare G Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E Abud, Georg Ramm, Antonella Papa, Andrew M Ellisdon, Roger J Daly, Catriona A McLean, Christina A Mitchell. INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer. Nature communications. 2021 May 25;12(1):3140