It was hypothesized that four histopathological types or subtypes of breast carcinoma were undifferentiated types characterized by bidirectional differentiation toward both luminal epithelial and myoepithelial cells and had characteristic molecular changes: invasive ductal carcinoma (IDC) with a large central acellular zone, atypical medullary carcinoma (a subgroup in Grade 3 solid-tubular carcinoma), matrix-producing carcinoma, and spindle-cell carcinoma (or carcinoma with spindle-cell metaplasia). In 32 cases of the undifferentiated type and 37 cases of the relatively differentiated types, we immunohistochemically examined the expressions of myoepithelial markers and KIT, epidermal growth factor receptor (EGFR), and c-erbB-2 oncoproteins. Vimentin, S-100, and α α α α-smooth muscle actin were positive in 28 (88%), 22 (69%), and 15 (47%) of the undifferentiated types, but were positive in seven (19%), one (3%), and one (3%) of relatively differentiated types (P < 0.0001). KIT and EGFR overexpressions were detected more frequently in the undifferentiated types (34 and 88%, respectively) than in relatively differentiated types (3 and 3%, respectively) (P < 0.0001, for both). In 11 (85%) of 13 cases with KIT overexpression, EGFR overexpression concurred. c-erbB-2 overexpression was almost equally detected in both the undifferentiated and relatively differentiated types, and did not correlate with KIT or EGFR overexpression. I n recent studies, mammary epithelial stem cells were shown to play roles in proliferation and remodeling of the mammary gland, and are also considered to be the primary targets for tumorigenesis in the adult mammary glands.(1) The stem cells also form the tumor stem-cell population. The mammary epithelial stem cells are undifferentiated cells and have potential of self-renewal by symmetrical or asymmetrical cell division and bidirectional differentiation to either luminal epithelial cells or myoepithelial cells through the stage of transit amplifying cells (or progenitor cells).(1) A stem cell is likely to be a small, undifferentiated cell that does not express markers of full differentiated myoepithelial and luminal epithelial cells, although the combinations of certain markers for both lineages have been suggested as being characteristics of the stem cells. In a previous study, we reported that the expression of myoepithelial cell markers, for example, vimentin, α-smooth muscle actin, and S-100 protein, were frequent in invasive ductal carcinoma (IDC) of solid-tubular subtype, nuclear grade 3, of the breast.(3) Vimentin, a mesenchymal marker, is also shown to be a molecule expressed by myoepithelial cells.(2) Therefore, it is compatible to consider that these immunophenotype observed in this breast carcinoma type would indicate its bidirectional differentiation toward luminal epithelial and myoepithelial cells.The KIT proto-oncogene encodes a growth factor receptor with tyrosine kinase activity and is involved in the growth and development of mast cells and of premature stromal cell or inter...