PIK3CA and breast cancer: Activity-enhancing protein kinase A may be involved in trastuzumab resistance via 3 pathways, this encompasses both direct stimulation of EGFR or PI3K, along with indirect activation of AKT through protein phosphatase 1(PP1) blockade.[164] Finally, fatty acid synthase confers resistance to trastuzumab in HER2-positive breast cancer via membrane lipid rafts,[165] polyomavirus enhancer activator 3, and ERα.[166–169]