The Origin and Significance of Mammary Intraductal Foam Cells

Intraductal foam cells are the most commonly encountered cells in spontaneous nipple discharge, aspirates, and lavage, and frequently surround DCIS and other intraductal proliferations. The origin of these cells is thus of potential importance, but is not presently understood. This project tested the hypothesis that these intraductal macrophages take origin from bone marrow-derived hematopoietic precursors. The central work tests the idea by transfer of bone marrow from C57BL6 mice recombinantly expressing green fluorescent protein GFP into wildtype GFP- recipients. After transfer, mice were hormonally manipulated for mammary epithelial stimulation, and evaluated for recruitment of GFP cells hematopoeitic origin associated with mammary epithelium. The prediction of foam cells with hematopoeitic origin was not confirmed. However, we showed that precursor cancer stem cells of hematopoeitic origin developed in mammary tissue with both benign and malignant differentiation, depending on environmental cues. Progression of the cells to cancer is associated with the up-regulation of c-kit and Sca-1, and was regulated by the PIWIAGO family gene piwil2. This demonstrates a surprising contribution of hematopoeitic precursors to the heterogeneity of cell types in benign and malignant mammary tissue.