Mammary Intraductal Foam Cells Are Bone Marrow Derived and Are Recruited in Response to Both Physiological as Well as Neoplastic Stimuli
SH Barsky, Y Xiao, Y Ye, K Yearsley. The Ohio State University College of Medicine, Columbus, OH
Background: Intraductal foam cells are the most commonly encountered cells in spontaneous nipple discharge, nipple aspirate fluid and ductal lavage yet their origin and significance remain a mystery. These cells increase in pregnancy and other conditions of ductal ectasia and obstruction. They frequently surround DCIS. These foam cells often ingest both endogenous as well as exogenous substances. Because these macrophages were observed intraductally and because their appearance resembled lactating, vacuolated epithelial cells, their origin had been assumed to be of ductal lining epithelium. Previous studies by us and others with macrophage (CD68, lysozyme), epithelial (cytokeratin, estrogen receptor) and myoepithelial (smooth muscle actin, CALLA, maspin) markers suggested that foam cells were of macrophage lineage and terminally differentiated (negative Ki-67 and PCNA). Because these observational IHC findings suggested a possible bone marrow-derived monocyte origin, we decide to conduct experimental studies to prove this hypothesis.
Design: We conducted two types of murine bone marrow transplant studies: Donor marrow from female GFP-transgenic C57 black mice were transplanted into sublethally irradiated female C57 recipients rendered pseudopregnant with a combination of estradiol, progesterone and estriol (2.5mg) 21 day release pellets. Donor marrrow from female ROSA26 containing the lacZ reporter were transplanted into irradiated female recipient transgenic mice carrying potent breast cancer oncogenes: the MMTV-pymT and the MMTV-erbb2/neu which result in breast cancer. Some of the transgenic recipients were also rendered pseudopregnant.
Results: In all of the transplanted recipient mice, the intraductal foam cells expressed the donor marker, either GFP or lacZ. However the number of donor-derived intraductal foam cells were increased in pseudopregnancy 10 fold, by intraductal neoplasia 5 fold and by a combination of the two over 25 fold. Ducts containing neoplastic cells with the highest numbers of mammary foam cells exhibited a significantly increased apoptotic index of the neoplastic cells by TUNEL.
Conclusions: The evidence of a bone marrow origin of mammary foam cells suggests a new strategy of delivering therapeutic genes to DCIS, other precancerous lesions or high risk ductal epithelium. This strategy would exploit the omnipresent mammary foam cell, its bone marrow origin and its chemoattraction to the breast in response to both physiological as well as neoplastic stimuli.
Monday, March 9, 2009 1:00 PM
Poster Session II # 61, Monday Afternoon