Abstract P6-01-08: Keratin 5/14+ Progenitor Cell Concept of Breast Epithelium: Revisited

Abstract

Abstract Background: The role of keratin (K) 5/14+ progenitor cells as precursor cells of the breast epithelium has been demonstrated both in culture and in situ. This cell model opens a new field in which distinct cell subtypes can be evaluated in terms of their functional state and describes how these cells may give rise to either benign or malignant tumors. Material and Methods: In this study, we used modern triple immunofluorescent labeling experiments to visualize directly different cell types and their functional status applying, as a reference, antibodies to basal (K5/14) and glandular (K8/18) keratins and a myoepithelial marker in combination with antibodies to ER-alpha, Ki67, BCL2 and c-kit in normal resting breast epithelium and in 30 cases of ductal neoplasia of low grade pathway and 8 cases of epithelial hyperplasia. Different cell types were quantitatively assayed. Immunolabeling results were supported with quantitative real time PCR. Results: Basal and glandular keratins in the normal luminal breast epithelium were found to be expressed in highly specific sequential pattern from K5/14+progenitor cells to K8/18+ glandular cells. ER alpha, Ki67, c-kit and BCL2 were found differentially expressed in various subtypes of the breast epithelium, ER-alpha was expressed only in a subset of glandular cells thus subdividing the glandular lineage into ER-alphapositive and negative subcategories. The highest Ki67-proliferation was found in phenotypically glandular cells which are ER-alpha negative. BCL2 was characteristically co-expressed in glandular cells, whereas c-kit was detected mainly in earlier glandular cells. Benign epithelial hyperplasia showed a striking similarity to normal luminal breast epithelium. In terms of functional differentiation these cells disclosed the same ER-alpha, BCL2 and c-kit expression as that observed in normal epithelium. In contrast to UDH, all types of low-grade in-situ neoplasia of ductal type are characterized by expression of only glandular keratins 8/18. The tumour cells co-expressed ER-alpha, BCL2 and Ki67. On the other hand, c-Kit was not expressed in these lesions. Discussion: From our data, it is evident that basal (K5/14) and glandular keratins (K8/18) are expressed in highly specific hierarchical patterns related to stage of glandular differentiation. This phenotypic hierarchy of cells is furthermore bound to a differential expression of ER, Ki67, c-kit and BCL2 in a very specific manner. Usual ductal hyperplasia disclosed a striking similarity to the resting glandular epithelium. In contrast, all types of low grade intraepithelial neoplasia not only retain the keratin patterns of their (normal) glandular counterpart but show the same functional differentiation with a positive expression of ER and BcL2 and lack of c-kit. This similarity indicates that these lesions may derive from more differentiated glandular cells of the lobular breast epithelium. The data presented here confirm that the K5/14+ progenitor cell concept provides important insight into the functional nature of normal breast epithelium and in proliferative diseases. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-08.