The immunohistochemically “ER-negative, PR-negative, HER2-negative, CK5/6-negative, and HER1-negative” subgroup is not a surrogate for the normal-like subtype in breast cancer

Breast cancer is a heterogeneous disease and can be subclassified into five major subtypes. The immunohistochemical (IHC) surrogates for four of the five subtypes have been developed by detection of ER, PR, HER2, HER1, and CK5/6 in breast cancers. To date, the IHC surrogate for the normal-like subtype is still ambiguous. However, some investigators treat the so-called “unclassified” IHC subgroup (negative for all the five markers) as the normal-like subtype. We have to understand that the normal-like subtype is absolutely different from the immunohistochemically “ER–, PR–, HER2–, CK5/6–, and HER1–” subgroup. Here, we show evidence to support the fact that low/negative expression of the basal-like markers is not the essence of the normal-like subtype. Moreover, a striking new finding has implied that the normal-like breast cancer subtype might play an important role in breast cancer initiation and development. Incorrect IHC definition of the normal-like subtype would compromise the understanding of the biological features and lead to a confused concept of this subtype.