Beyond the overlapping downstream activation of PI3K/AKT and MAPK signaling cascades present in ER+ breast cancer cells overexpressing HER2 [16,17,18], which also acquire an endocrine-resistant phenotype, the definitive mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer cells are largely unknown. This evidence concerns the gene ESR1 and breast carcinoma.