A late endosome signaling hub that couples PI3Kα and WNT/ß-catenin signaling in breast cancer.

ABSTRACT

AKT is the central phosphoinositide 3-kinase (PI3K) signaling effector, however, PIK3CA (p110α subunit of PI3Kα)-mutant estrogen receptor-positive (ER+) breast cancers exhibit minimal AKT activation and the downstream signaling is poorly characterized. We discovered that a subset of PIK3CA-mutant ER+ breast cancers exhibit increased inositol polyphosphate 4-phosphatase type II (INPP4B) expression, which promotes late endosome formation and glycogen synthase kinase 3 beta (GSK3ß) trafficking, leading to enhanced Wingless-related integration site (WNT)/catenin beta 1 (ß-catenin) activation.