Abstract
Elucidating the phenotypic evolution of breast cancer through distinct subtypes relies heavily on defining a lineage blueprint of the normal human breast. Here, we show that in normal breast, within the luminal epithelial lineage, a subset of cells characterized by strong staining for endocrine receptors are also characterized by expression of the surface marker CEACAM6. Topographically, this pattern of staining predominates in terminal ductal lobular units, rather than in interlobular ducts. In culture, CEACAM6-expressing cells remain essentially postmitotic under conditions in which the other cells of luminal epithelial lineage are highly proliferative. We examined the pattern of expression among three major breast cancer subtypes: luminal, HER2-enriched, and basal-like. In 104 biopsies, the luminal and HER2-enriched subtypes showed a high proportion of CEACAM6(+) tumors (78% and 83%, respectively); the basal-like subtype showed a low proportion (28%). Further accentuation of this pattern was observed in 13 established breast cancer cell lines. When differentiation was induced by all-trans retinoic acid, CEACAM6 expression strongly correlated with luminal-like differentiation. Furthermore, CEACAM6(+) cancer cells were less proliferative than CEACAM6(-) cells in tumorsphere assays and were less tumorigenic in nude mice. Based on these observations, we propose that luminal and HER2-enriched breast cancers are more closely related than previously thought and may share a common cell of origin.