Figure 3. WWP1 expression is upregulated in isogenic breast cancer cells resistant to PI3K inhibitors.
(A) Evaluation of WWP1 and Myc expression, and activity of the downstream PI3K pathway in isogenic resistant MDA-MB-231 and MCF7 cells. A set of isogenic resistant cells was sequentially established by repeating exposure to stepwise increasing concentrations of BKM120. Generated clones were maintained in BKM120-containing media. For the experiment, cells were cultured with BKM120-free media for 24 hours and harvested for WB. (B) Endogenous PTEN ubiquitination in isogenic MDA-MB-231 cells. Extracted lysates were pulled down by anti-PTEN antibody. (C) Activation of AKT and S6 in MDA-MB-231 cells with stable overexpression of WWP1 upon BKM120 treatment. Total lysates were resolved by SDS-PAGE and subsequently probed with the indicated antibodies. EV, control empty vector. (D and E) Dose response curve of BKM120 in MDA-MB-231 (D) and BYL719 in MCF7 (E) cells with stable overexpression of HA-WWP1. (F and G) Dose response curve of BKM120 in resistant MDA-MB-231 HD cells (F) and BYL719 in resistant MCF7 HD cells (G) with WWP1 shRNA. Each dot indicates the mean ± SD of a duplicated assay.