Dataset Information

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

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.

SUBMITTER: Rodgers SJ

PROVIDER: S-EPMC8149851 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Rodgers Samuel J SJ Ooms Lisa M LM Oorschot Viola M J VMJ Schittenhelm Ralf B RB Nguyen Elizabeth V EV Hamila Sabryn A SA Rynkiewicz Natalie N Gurung Rajendra R Eramo Matthew J MJ Sriratana Absorn A Fedele Clare G CG Caramia Franco F Loi Sherene S Kerr Genevieve G Abud Helen E HE Ramm Georg G Papa Antonella A Ellisdon Andrew M AM Daly Roger J RJ McLean Catriona A CA Mitchell Christina A CA

Nature communications 20210525 1

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 cel ...[more]

PMID: 34035258

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Dataset Information

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

Publications

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

Similar Datasets

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