Fig. 7: Mutant PIK3CA promotes increased Wnt gene expression through INPP4B.

a Expression of a panel of 17 Wnt pathway genes was assessed in 1469 ER⁺ breast cancers from the METABRIC cohort, and stratified by PIK3CA-mutation status. The center line indicates the median, the lower bound of the box indicates the 25th percentile, the upper bound of the box represent the 75th percentile, the lower whisker extends from the 25th percentile to the 5th percentile, and the upper whisker extends from the 75th percentile to the 95th percentile. b–d MCF-7 cells expressing GFP-INPP4B or GFP-vector were treated with BKM120 (0.5 or 1 µM) or DMSO as a vehicle control for 48 h, then RNA was extracted two-step quantitative RT-PCR was performed using primers for AXIN2 (b), MYCN (c), or LEF1 (d). Expression was normalized to RRN18S. Expression was determined using the ΔΔCt method and expressed relative to vehicle-treated GFP-vector control cells (±SD), which were assigned an arbitrary value of 1 (n = 3 experiments). e Model of PI3Kα and Wnt/β crosstalk via INPP4B-mediated late endosome formation. In PIK3CA-mutant ER⁺ breast cancers, INPP4B is upregulated and localizes to the late endosome via its interaction with Rab7, which enhances its PI(3,4)P₂ 4-phosphatase activity. INPP4B converts PI(3,4)P₂ to PI(3)P downstream of PI3Kα, which promotes Hrs-mediated late endosome formation, and increases the lysosomal degradation of GSK3β bound to the β-catenin destruction complex, promoting activation of Wnt/β-catenin signaling. p values determined by unpaired two-tailed Mann–Whitney test in a, or by one-way ANOVA with Tukey post hoc test in b, c, d.