Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype

Significance HER2+ breast cancers (BrCs) are heterogeneous, but they are treated as a single type. Using a mouse model with Erbb2 (the rodent homolog of HER2)-induced BrC and cell lineage-tracing capacity, we found that ERα+ Erbb2+ cancer cells proliferate slowly and are nonmetastatic but then progressively lose ERα expression to become fast proliferating and highly metastatic ERα− Erbb2+ cancer cells. ERα− Erbb2+ cancer cells with an ERα− origin proliferate fast, but they metastasize weakly. These findings suggest: 1) ERα expression should be preserved in ERα+ HER2+ BrCs to restrict growth and metastasis; 2) ERα− HER2+ BrCs contain a highly metastatic subtype with an ERα+ origin and a weakly metastatic subtype with an ERα− origin, indicating a future need to identify and differentially treat these two subtypes.