A number of recent studies have suggested that the
colony-stimulating factor (CSF-1) and its receptor c-fms may be involved in the development of mammary glands during lactation and
breast cancer. To study the role of
CSF-1 or its receptor in initiation of mammary
tumorigenesis, we have generated two independent lines of transgenic mice that overexpress either
CSF-1 or c-fms under the control of the mouse mammary tumor virus promoter. Mammary glands of the virgin
CSF-1 transgenic mice show increased ductal branching,
hyperplasia, dysplasia, and other preneoplastic changes, which are indicative of increased cellular proliferation. Similar changes were also evident in the mammary glands of the c-fms transgenic mice. These changes became more prominent with age and resulted in mammary
tumor formation. Moreover, secondary events like dimethylbenz(a)
anthracene treatment accelerated mammary
tumor formation in these mice. Although the expression of
estrogen receptor alpha was not significantly changed in either of the transgenic mouse strains,
progesterone receptor levels was higher in both transgenic lines as compared with the nontransgenic littermates. Expression of G1
cyclins was prominently increased in the mammary glands of both the
CSF-1 and c-fms transgenic lines, suggesting increased cell cycle progression in these strains. In addition, the proliferation marker
proliferating cell nuclear antigen (
PCNA) and the
mitogen-responsive
transcription factor c-jun were also increased as compared with the nontransgenic controls. These findings, along with the histological data, support the hypothesis that
CSF-1 and its receptor are involved in the etiology of
breast cancer.