We have developed a series of novel mammary epithelial cell lines from
tumors arising in strain 129 mice, with the ultimate goal of evaluating the role of host factors in the development of bone
metastases. Mammary
tumors were induced in mice with subcutaneously implanted
medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary
tumor development was efficient in the 129 strain and was independent of
osteopontin (OPN) expression. Epithelial cell lines were isolated from these
tumors; surprisingly, these cells did not form
tumors upon inoculation into the mammary fat pad of syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft
agar, and formed
hormone-independent
tumors efficiently in the mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from
tumors arising in the fat pad and from a lung
metastasis (r3T and r3L, respectively): these cells formed
tumors more rapidly in the fat pad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone
metastases in 129 mice, with few
metastases seen in other organs. These
tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone
metastases were not seen on x-ray; instead extensive liver
metastasis was present in these mice, indicating that genetic factors in these two strains regulate
tumor cell homing and distribution during
metastasis. These cell lines provide an important new tool in the study of bone
metastasis, particularly in elucidating the role of host factors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.