Details

Autor(en) / Beteiligte

• Rodgers, 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.

Titel

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

Ist Teil von

• Nature communications, 2021-05, Vol.12 (1), p.3140-3140, Article 3140

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. The PI(3,4)P 2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA -mutant ER +  breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling.