Though Mulholland and Carver proposed somewhat different mechanisms, they independently demonstrated with both pharmacologic and genetic approaches PI3K/AKT activation via PTEN loss promotes prostate cancer growth in the absence of AR signaling; as a result, they hypothesize that strong suppression of AR-signaling with potent anti-androgen therapy may select for tumors with PI3K pathway activation and repressed AR activity leading to CRPC. This evidence concerns the gene PIK3CD and Familial prostate cancer.