Abstract P4-01-18: A discrete population of p63+/K5/14+ cells implicated in the pathogenesis of salivary gland-like tumors of the breast

Abstract

Abstract Background: Salivary gland-like tumors are currently subdivided into those with and those without myoepithelial differentiation. Furthermore, they show a wide range of differentiation patterns including squamous differentiation. Many authors believe that the myoepithelial cell plays a major role in this context. However, currently little is known about the evolution and cellular differentiation of these tumors. Material and Methods: For that reason, we performed an in situ Triple Immunofluorescence Lineage/Differentiation Tracing (isTILT) and qRT-PCR study of basal (K5/K14), glandular (K7/K8/18), and epidermal-specific squamous (K10) keratins, p63, and smooth muscle actin (SMA; myoepithelial marker) with the aim to trace different cell lineages and define their cellular hierarchy in tumors. We investigated 50 cases of salivary gland-like tumors of the breast (11 Adenoid-cystic carcinomas, 9 (adeno-)myoepithelial tumors, 8 adeno-squamous carcinomas including 12 syringomas of the nipple, 10 squamous cell carcinomas), and their corresponding counterparts. In 4 cases, the corresponding cell cultures were also analysed. Results: All tumor types contained p63+/K5/14+ progenitor cells in varying frequencies from a few percent up to 15%. These tumor cells were found to differentiate to glandular (K8/18-positive) or to myoepithelial (SMA-positive) lineage specific cells; they were also shown to generate various heterologeous cell differentiations such as squamous and mesenchymal progenies. p63 was partly retained in the myoepithelial and squamous cells lineages but not in the glandular cells lineage. These data were corroborated by RNA-expression results. The corresponding counterpart tumors of the salivary/lacrimal glands were found to have identical cellular compositions. Conclusions: Our findings clearly demonstrate that p63+/K5/14+ tumor cells in salivary gland-like tumors of the breast and in their counterparts are key players in tumor development and differentiation. They undergo a transition from their original p63+/K5/14+ precursor state to new p63+/K5/14+/SMA+ myoepithelial and/or p63+/K10+ squamous lineages, and/or to a K7+/K8/18+ glandular state, which can be pictured by isTILT-experiments and RNA-expression studies. Given the phenotypic similarity of p63+/K5/14+ tumor cells to physiological counterparts in the normal breast and salivary duct epithelium and considering the fact that these cells may give rise to a number of different progenies with specific differentiation lineages, we suggest that this cell and its physiological differentiation potential provides an important ontogenetic key to a better understanding of these tumors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-18.