Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23241-6
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Funding
- NHMRC [APP1104614]
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INPP4B functions as a tumor suppressor in triple negative breast cancer by converting PI(3,4)P-2 to PI(3)P. However, in PIK3CA-mutant ER+ breast cancers, INPP4B enhances cell proliferation and tumor growth by promoting PI3K alpha-dependent late endosome formation and trafficking that activates Wnt/beta -catenin signaling.
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 PI3K alpha -dependent PI(3,4)P-2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3 beta lysosomal degradation and activation of Wnt/beta -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 PI3K alpha 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/beta -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 PI3K alpha -dependent late endosome formation and trafficking that leads to the activation of Wnt/beta -catenin signalling.
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