Discordant estrogen receptor alpha (ER) expression in occasional breast cancers strongly suggests that mechanisms exist that are responsible for the evolution of ER-negative from ER-positive tumor cells. For example, nearly all invasive breast cancers (IBCs) contain varying proportions of ductal carcinoma in situ (DCIS), probably representing residual precursors. (a) In ~5% of ER-negative IBCs, the DCIS component is strongly ER-positive. As another example, histologically high-grade DCIS are often (~70%) ER-negative. (b) A diligent search can reveal foci of lower-grade/ER-positive DCIS in the same breast, which may be a precursor to the higher-grade/ER-negative component.