Frequent KIT and epidermal growth factor receptor overexpressions in undifferentiated‐type breast carcinomas with ‘stem‐cell‐like’ features

Abstract

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...

Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3

“…In ovarian serous carcinoma, c-Kit was only expressed in high-grade poorly differentiated tumors, and was absent in low-grade well-differentiated tumors, suggesting a correlation with malignant progression [29]. Similarly, in the invasive ductal carcinoma type of breast cancer, c-Kit overexpression was almost exclusively expressed in the undifferentiated tumors with 'stem cell like' features [30] [31]. Further study is needed to identify the tumorinitiating capacity of CD133 þ CD117 þ cells compared with…”

Basoluminal Carcinoma: A New Biologically and Prognostically Distinct Entity Between Basal and Luminal Breast Cancer

“…Although both subtypes clearly shared the major features of the basal cytokeratin -positive tumors (hormone receptor negativity and high tumor grade), the basal tumors were more often positive for vimentin and c-kit, which suggests that the uniformly CK5/14-positive basal tumors represent an entity that more closely resembles the primitive breast epithelium progenitor cell (14,16,19,31,32). The basoluminal tumors may represent an entity that is intermediate between uniformly CK5/14-positive basal tumors and totally CK5/14-negative luminal tumors.…”

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

“…Genes upregulated more than fivefold in the mammary glands of MMTV-Cre Brca1 Co/Co mice at day 1 of lactation include Cdkn1A (p21, up 16.3-fold), a cell cycle regulated that has previously been shown to be upregulated upon Brca1 repression (Hakem et al, 1996) and that has been implicated in breast cancer (Weiss, 2003); interferon-stimulated gene 15 (Isg15, up 10.9-fold) and the gene encoding the Isg15-interacting protein Ubp43 (up eightfold), the former being a ubiquitin-like gene implicated in immune response to viruses and in breast cancer (Bektas et al, 2008); oligoadenylate synthetase 1G (up 9.2-fold) and 1A (up 5.7-fold), an interferon-induced enzyme implicated in nucleotide metabolism and expressed in the mammary gland (Maia et al, 2008) and induced upon irradiation of human breast cancer cell lines (Tsai et al, 2007); and c-kit (up 5.58-fold), a hematopoietic stem cell marker that is overexpressed in undifferentiated mammary tumours (Tsuda et al, 2005) and functions as an oncogene in mammary epithelial cells (Tsuda et al, 2005;Raafat et al, 2007). Taken together, these genes suggest a role for Brca1 in the immune response and cancer.…”