ESR1 and breast cancer: The multistep model of breast cancer progression [1, 2] contends that although lobular carcinomas arise along the low-grade, ER-positive arm of the pathway (with low-grade, ER-positive ductal lesions), de-differentiation to higher grade lesions can occur through acquisition of alterations in oncogenes such as ERBB2 and TP53, producing a spectrum of heterogenous proliferations (Fig. 1).