Conditionally reprogrammed normal and transformed mouse mammary epithelial cells display a progenitor-cell-like phenotype.
Mammary epithelial (ME) cells cultured under conventional conditions senesce after several passages. Here, we demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neu-induced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs) on irradiated fibroblasts in the presence of the Rho kinase inhibitor Y-27632. Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells. However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+, and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation. Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Francisco R
FR
Saenz
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Virginie
V
Ory
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Maram
M
AlOtaiby
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Sonia
S
Rosenfield
Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Mary
M
Furlong
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Luciane R
LR
Cavalli
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Michael D
MD
Johnson
Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Xuefeng
X
Liu
Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Richard
R
Schlegel
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Anton
A
Wellstein
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, United States of America.
Anna T
AT
Riegel
D000577:Amides / Q000737:chemistry; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D055028:Comparative Genomic Hybridization; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology*; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D008321:Mammary Glands, Animal / Q000166:cytology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010641:Phenotype; D011509:Proteoglycans / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D013234:Stem Cells / Q000166:cytology
D000577:Amides; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D011509:Proteoglycans; D011725:Pyridines; C059485:matrigel; C108830:Y 27632; D003094:Collagen