In addition to ER that can activate HER signaling [62], alterations of INPP4-B (inositol polyphosphate 3-kinase-phosphatase, type II) and PTEN (a natural inhibitor of Pi3K), or activating mutations in PIK3CA also activate HER2 and may account for resistance to therapies targeting HER2 [The cancer genome atlas network, 2012; 63]. The gene discussed is ESR1; the disease is cancer.