Ectopic expression of the Ets transcription factor ER81 in transgenic mouse mammary gland enhances both urokinase plasminogen activator and stromelysin-1 transcription

The PEA3 group members PEA3, ER81 and ERM, which are highly conserved transcription factors from the Ets family, are over-expressed in metastatic mammary tumors. In the current study, we present the characterization of a transgenic mouse strain which over-expresses ER81 in the mammary gland via the long terminal repeat of the mouse mammary tumor virus (LTR-MMTV). Although six genotypically positive transgenic lines were identified, only one expressed the ectopic transcript with an exclusive expression in the lactating and late-pregnancy (18th day) mammary glands. No mammary tumor or mammary deregulation appeared after 2 years of ectopic ER81 expression following lactation. We then sought to identify ER81 target genes, and the urokinase plasminogen activator (uPA) and the stromelysin-1, two enzymes involved in extracellular matrix degradation, were found to be transcriptionally upregulated in lactating mammary glands over-expressing ER81. Since these enzymes are involved in metastasis, this murine model could be further used to enhance mammary cancer metastatic process by crossing these animals with mice carrying non-metastatic mammary tumors. We thus created a transgenic mouse model permitting the over-expression of a functionally active Ets transcription factor in the mammary gland without perturbing its development.

Androgens and breast cancer

We have recently demonstrated that physiological levels of androgens exert direct and potent inhibitory effects on the growth of human breast cancer ZR-75-1 cells in vivo in nude mice as well as in vitro under both basal and estrogen-stimulated conditions. The inhibitory effect of androgens has also been confirmed on the growth of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. Such observations are in close agreement with the clinical data showing that androgens and the androgenic compound medroxyprogesterone acetate (MPA) have beneficial effects in breast cancer in women comparable to other endocrine therapies, including tamoxifen. Although the inhibitory action of androgens on cell proliferation in estrogen-induced ZR-75-1 cells results, in part, from their suppressive effect on expression of the estrogen receptor, the androgens also exert a direct inhibitory effect independent of estrogens. Androgens cause a global slowing effect on the duration of the cell cycle. These observations support clinical data showing that androgenic compounds induce an objective remission after failure of antiestrogen therapy as well as those indicating that the antiproliferative action of androgens is additive to that of antiestrogens. We have also recently demonstrated in ZR-75-1 human breast cancer cells the antagonism between androgens and estrogens on the expression of GCDFP-15 and GCDFP-24 which are two major proteins secreted in human gross cystic disease fluid. The effects of androgens and estrogens as well as those of progestins and glucocorticoids on GCDFP-15 and GCDFP-24 mRNA levels and secretion are opposite to those induced by the same steroids on cell growth in ZR-75-1 cells.