However, a variety of other mechanisms leading to intrinsic or aquired resistance to HER2-targeting therapies that are independent of ERα status have been observed among HER2+ breast cancer patients [46], including low PTEN expression, oncogenic PI3CA mutations [47], up-regulation of growth factor receptors such as other HER-family members, IGF-R1 [48], EphA2 [49], Met [50] and Axl [51]. This evidence concerns the gene ERBB2 and breast cancer.