| Literature DB >> 34035258 |
Samuel J Rodgers1,2, Lisa M Ooms1,2, Viola M J Oorschot3,4, Ralf B Schittenhelm5, Elizabeth V Nguyen1,2, Sabryn A Hamila1,2, Natalie Rynkiewicz2,6, Rajendra Gurung1,2, Matthew J Eramo1,2, Absorn Sriratana1,2, Clare G Fedele2,7, Franco Caramia7, Sherene Loi7, Genevieve Kerr8,9, Helen E Abud8,9, Georg Ramm1,2,3, Antonella Papa1,2, Andrew M Ellisdon1,2,10, Roger J Daly1,2, Catriona A McLean11, Christina A Mitchell12,13.
Abstract
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.Entities:
Year: 2021 PMID： 34035258 DOI： 10.1038/s41467-021-23241-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919